Abstracts of Articles in 2010


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  1. Protein structural flexibility: molecular motions.
  2. Computation of Non-covalent Binding Affinities.
  3. Rapid Estimation of Solvation Energy for Simulations of Protein-Protein Association.
  4. Release of ADP from the catalytic subunit of protein kinase A: A molecular dynamics simulation study.
  5. Phosphorylation effects on cis/trans isomerization and the backbone conformation of serine-proline motifs: Accelerated molecular dynamics analysis.
  6. How does the cAMP-Dependent Protein Kinase Catalyze the Phosphorylation Reaction: an ab initio QM/MM Study.
  7. Ligand-Induced Conformational Change in the α7 Nicotinic Receptor Ligand Binding Domain.
  8. Agonist-mediated conformational changes in ACh-binding protein revealed by simulation and intrinsic tryptophan fluorescence.
  9. Tetrameric Mouse Acetylcholinesterase: Continuum Diffusion Rate Calculations by Solving the Steady-State Smoluchowski Equation Using Finite Element Methods.
  10. Relative contributions of desolvation, inter- and intramolecular interactions to binding affinity in protein kinase systems.
  11. Acetylcholinesterase: Pivotal Roles of its Long Omega Loop (Cys69-Cys96) in Regulating Binding.
  12. A gating mechanism proposed from a simulation of a human α7 nicotinic acetylcholine receptor.
  13. Substrate concentration dependence of the diffusion-controlled steady-state rate constant.
  14. Pushing the limits: Editorial overview.
  15. Optimized radii for Poisson-Boltzmann calculations with the AMBER force field.
  16. Computation of electrostatic forces between solvated molecules determined by the Poisson-Boltzmann equation using a boundary element method.
  17. The folding energy landscape and phosphorylation: modeling the conformational switch of the NFAT regulatory domain.
  18. Relating kinetic rates and local energetic roughness by accelerated molecular dynamics simulations.
  19. Exploring Global Motions and Correlations in the Ribosome.
  20. A coarse grained model for the dynamics of the early stages of the binding mechanism of HIV-1 Protease.
  21. Exploring Assembly Energetics of the 30S Ribosomal Subunit Using an Implicit Solvent Approach.
  22. Molecular Docking of Balanol to Dynamics Snapshots of Protein Kinase A.
  23. The Entropic Cost of Protein-Protein Association: A Case Study on Acetylcholinesterase Binding to Fasciculin-2.
  24. Limitations of Atom-Centered Dielectric Functions in Implicit Solvent Models.
  25. Calculation of the Maxwell stress tensor and the Poisson-Boltzmann force on a solvated molecular surface using hypersingular boundary integrals.
  26. Target Flexibility in Molecular Recognition.
  27. Fast Peptidyl cis-trans Isomerization within the Flexible Gly-Rich Flaps of HIV-1 Protease
  28. Potent, Selective Pyrone-Based Inhibitors of Stromelysin-1.
  29. Induced Fit in Mouse Acetylcholinesterase upon Binding a Femtomolar Inhibitor: A Molecular Dynamics Study.
  30. The Association of Tetrameric Acetylcholinesterase with ColQ Tail: A Block Normal Mode Analysis.

Back to McCammon Group: Publications


Protein structural flexibility: molecular motions

Richard H. Henchman and J. Andrew McCammon

In "Encyclopedia of Life Sciences," John Wiley and Nature Publishing Group (2005)

Protein molecules are intrinsically flexible and typically undergo a wide variety of motions at normal temperatures. The flexibility and dynamics of proteins have been harnessed by evolution for a wide variety of their activities, ranging from ligand binding to regulation of function.


Computation of Non-covalent Binding Affinities

J. Andrew McCammon

In "Theory and Applications of Computational Chemistry," C. Dykstra, G. Frenking, K. Kim, and G. Scuseria, Eds., Elsevier, Amsterdam, Ch. 3, pp. 41-46 (2005)

The ability to accurately predict and analyze molecular recognition is being achieved by advances in several areas of theoretical chemistry and related fields such as applied mathematics and computational science. This chapter provides an overview of the history, current state and future prospects for computational studies of molecular recognition.


Rapid Estimation of Solvation Energy for Simulations of Protein-Protein Association

David S. Cerutti, Lynn F. Ten Eyck and J. Andrew McCammon

Journal of Chemical Theory and Computation, Vol. 1, No. 1, pp. 143-152 (2005)

We have formulated the Energy by Linear Superposition of Corrections Approximation (ELSCA) for estimating the electrostatic and apolar solvation energy of bringing two proteins into close proximity or into contact as defined by the linearized Poisson-Boltzmann model and a linear function of the solvent-accessible surface area. ELSCA utilizes potentials of mean force between atom types found in the AMBER ff99 force field, a uniform distance-dependent dielectric, and a potential that mimics the change in solvent accessible surface area for bringing two solvated spheres into contact. ELSCA was trained by a linear least-squares fit on more than 39 000 putative complexes, each formed from pairs of nonhomologous proteins with a range of shapes, sizes, and charges. The training set was also designed to capture various stages of complex formation. ELSCA was tested against over 8000 non-native complexes of 45 enzyme/inhibitor, antibody/antigen, and other systems that are known to form complexes and gives an overall correlation of 0.962 with PBSA-derived energies for these complexes. The predictions have a slope of 0.89 on the actual values with a bias of 11.1 kcal/mol. When applied to native complexes of these 45 protein systems, ELSCA reproduces PBSA results with a correlation of 0.787, a slope of 1.13, and a bias of 13.0 kcal/mol. We report parameters for ELSCA in the context of the AMBER ff99 parameter set. Our model is most useful in macromolecular docking and protein association simulations, where large portions of each molecule may be considered rigid.


Release of ADP from the catalytic subunit of protein kinase A: A molecular dynamics simulation study

Benzhuo Lu, Chung F. Wong and J. Andrew McCammon

Protein Science, Vol. 14, Issue 1, pp. 159-168 (2005)

[PubMed: 15608120]

Substrate phosphorylation by cAMP-dependent-protein kinase A (protein kinase A, PKA) has been studied extensively. Phosphoryl transfer was found to be fast, whereas ADP release was found to be the slow, rate-limiting step. There is also evidence that ADP release may be preceded by a partially rate-limiting conformational change. However, the atomic details of the conformational change and the mode of ADP release are difficult to obtain experimentally. In this work, we studied ADP release from PKA by carrying out molecular dynamics simulations with different pulling forces applied to the ligand. The detailed ADP release pathway and the associated conformational changes were analyzed. The ADP release process was found to involve a swinging motion with the phosphate of ADP anchored to the Gly-rich loop, so that the more buried adenine base and ribose ring came out before the phosphate. In contrast to the common belief that a hinge-bending motion was responsible for the opening of the ligand-binding cleft, our simulations showed that the small lobe exhibited a large amplitude "rocking" motion when the ligand came out. The largest conformational change of the protein was observed at about the first quarter time point along the release pathway. Two prominent intermediate states were observed in the release process.


Phosphorylation effects on cis/trans isomerization and the backbone conformation of serine-proline motifs: Accelerated molecular dynamics analysis

Donald Hamelberg, Tongye Shen and J. Andrew McCammon

Journal of the American Chemical Society, Vol. 127, No. 6, pp. 1969-1974 (2005)

[PubMed: 15701032]

The presence of serine/threonine-proline motifs in proteins provides a conformational switching mechanism of the backbone through the cis/trans isomerization of the peptidyl-prolyl () bond. The reversible phosphorylation of the serine/threonine modulates this switching in regulatory proteins to alter signaling and transcription. However, the mechanism is not well understood. This is partly because cis/trans isomerization is a very slow process and, hence, difficult to study. We have used our accelerated molecular dynamics method to study the cis/trans proline isomerization, preferred backbone conformation of a serine-proline motif, and the effects of phosphorylation of the serine residue. We demonstrate that, unlike normal molecular dynamics, the accelerated molecular dynamics allows for the system to escape very easily from the trans isomer to cis isomer, and vice versa. Moreover, for both the unphosphorylated and phosphorylated peptides, the statistical thermodynamic properties are recaptured, and the results are consistent with experimental values. Isomerization of the proline bond is shown to be asymmetric and strongly dependent on the backbone angle before and after phosphorylation. The rates of escape decrease after phosphorylation. Also, the -helical backbone conformation is more favored after phosphorylation. This accelerated molecular dynamics approach provides a general approach for enhancing the conformational transitions of molecular systems without having prior knowledge of the location of the minima and barriers on the potential-energy landscape.


How does the cAMP-Dependent Protein Kinase Catalyze the Phosphorylation Reaction: an ab initio QM/MM Study

Yuhui Cheng, Yingkai Zhang and J. Andrew McCammon

Journal of the American Chemical Society, Vol. 127, No. 5, pp. 1553-1562 (2005)

[PubMed: 15686389]

We have carried out density functional theory QM/MM calculations on the catalytic subunit of cAMP-dependent protein kinase (PKA). The QM/MM calculations indicate that the phosphorylation reaction catalyzed by PKA is mainly dissociative, and Asp166 serves as the catalytic base to accept the proton delivered by the substrate peptide. Among the key interactions in the active site, the Mg2+ ions, glycine rich loop, and Lys72 are found to stabilize the transition state through electrostatic interactions. On the other hand, Lys168, Asn171, Asp184, and the conserved waters bound to Mg2+ ions do not directly contribute to lower the energy barrier of the phosphorylation reaction, and possible roles for these residues are proposed. The QM/MM calculations with different QM/MM partition schemes or different initial structures yield consistent results. In addition, we have carried out 12 ns molecular dynamics simulations on both wild type and K168A mutated PKA, respectively, to demonstrate that the catalytic role of Lys168 is to keep ATP and substrate peptide in the near-attack reactive conformation.


Ligand-Induced Conformational Change in the α7 Nicotinic Receptor Ligand Binding Domain

Richard H. Henchman, Hai-Long Wang, Steven M. Sine, Palmer Taylor and J. Andrew McCammon

Biophysical Journal, Vol. 88, No. 4, pp. 2564-2576 (2005)

[PubMed: 15665135]

Implicit solvent models are a standard tool for assessing the electrostatics of biomolecular systems. The accuracy of quantitative predictions, such as pKa values, transfer free energies, binding energies, and solvation forces, is strongly dependent on one's choice of continuum parameters: the solute charges, dielectric coefficient, and radii, which define the dielectric boundary. To ensure quantitative accuracy, these parameters can be benchmarked against explicit solvent simulations. Here we present two sets of optimized radii to define either abrupt or cubic-spline smoothed dielectric boundaries in Poisson-Boltzmann calculations of protein systems with AMBER (parm99) charges. Spline smoothing stabilizes the electrostatic potential at the molecular surface, allowing for continuum force calculations. Most implementations, however, require significantly different radii than the abrupt boundary surfaces. The optimal continuum radii are initially approximated from the solvent radial charge distribution surrounding each atom type. A genetic algorithm is then used to fine-tune the starting values to reproduce charging free energies measured from explicit solvent simulations. The optimized radii are tested on four protein-like polypeptides. The results show increased accuracy of molecular solvation energies and atomic forces relative to commonly used continuum parameter sets. These radii are suitable for Poisson-Boltzmann calculations with the AMBER force field and offer energetic congruence to any model that combines molecular mechanics and Poisson-Boltzmann solvation energies.


Agonist-mediated conformational changes in ACh-binding protein revealed by simulation and intrinsic tryptophan fluorescence

Fan Gao, Nina Bren, Thomas P. Burghardt, Scott Hansen, Richard H. Henchman, Palmer Taylor, J. Andrew McCammon and Steven M. Sine

Journal of Biological Chemistry, Vol. 280, Issue 9, pp. 8443-8451 (2005)

[PubMed: 15591050]

We delineated acetylcholine (ACh)-dependent conformational changes in a prototype of the nicotinic receptor ligand binding domain by molecular dynamics simulation and changes in intrinsic tryptophan (Trp) fluorescence. Prolonged molecular dynamics simulation of ACh-binding protein showed that binding of ACh establishes close register of Trps from adjacent subunits, Trp143 and Trp53, and draws the peripheral C-loop inward to occlude the entrance to the binding cavity. Close register of Trp143 and Trp53 was demonstrated by ACh-mediated quenching of intrinsic Trp fluorescence, elimination of quenching by mutation of one or both Trps to Phe, and decreased lifetime of Trp fluorescence by bound ACh. Occlusion of the binding cavity by the C-loop was demonstrated by restricted access of an extrinsic quencher of binding site Trp fluorescence by ACh. The collective findings showed that ACh initially establishes close register of conserved Trps from adjacent subunits and then draws the C-loop inward to occlude the entrance to the binding cavity.


Tetrameric Mouse Acetylcholinesterase: Continuum Diffusion Rate Calculations by Solving the Steady-State Smoluchowski Equation Using Finite Element Methods

Deqiang Zhang, Jason Suen, Yongjie Zhang, Yuhua Song, Zoran Radić, Palmer Taylor, Michael J. Holst, Chandrajit Bajaj, Nathan A. Baker and J. Andrew McCammon

Biophysical Journal, Vol. 88, No. 3, pp. 1659-1665 (2005)

[PubMed: 15626705]

The tetramer is the most important form for acetylcholinesterase in physiological conditions, i.e., in the neuromuscular junction and the nervous system. It is important to study the diffusion of acetylcholine to the active sites of the tetrameric enzyme to understand the overall signal transduction process in these cellular components. Crystallographic studies revealed two different forms of tetramers, suggesting a flexible tetramer model for acetylcholinesterase. Using a recently developed finite element solver for the steady-state Smoluchowski equation, we have calculated the reaction rate for three mouse acetylcholinesterase tetramers using these two crystal structures and an intermediate structure as templates. Our results show that the reaction rates differ for different individual active sites in the compact tetramer crystal structure, and the rates are similar for different individual active sites in the other crystal structure and the intermediate structure. In the limit of zero salt, the reaction rates per active site for the tetramers are the same as that for the monomer, whereas at higher ionic strength, the rates per active site for the tetramers are 67% - 75% of the rate for the monomer. By analyzing the effect of electrostatic forces on ACh diffusion, we find that electrostatic forces play an even more important role for the tetramers than for the monomer. This study also shows that the finite element solver is well suited for solving the diffusion problemwithin complicated geometries.


Relative contributions of desolvation, inter- and intramolecular interactions to binding affinity in protein kinase systems

Peter A. Sims, Chung F. Wong, Danka Vuga, J. Andrew McCammon and Bartholomew M. Sefton

Journal of Computational Chemistry, Vol. 26, Issue 7, pp. 668-681 (2005)

[PubMed: 15754303]

In several previous studies, we performed sensitivity analysis to gauge the relative importance of different atomic partial charges in determining protein-ligand binding. In this work, we gain further insights by decomposing these results into three contributions: desolvation, intramolecular interactions, and intermolecular interactions, again based on a Poisson continuum electrostatics model. Three protein kinase-inhibitor systems have been analyzed: CDK2-deschloroflavopiridol, PKA-PKI, and LCK-PP2. Although our results point out the importance of specific intermolecular interactions to the binding affinity, they also reveal the remarkable contributions from the solvent-mediated intramolecular interactions in some cases. Thus, it is necessary to look beyond analyzing protein-ligand interactions to understand protein-ligand recognition or to gain insights into designing ligands and proteins. In analyzing the contributions of the three components to the overall binding free energy, the PKA-PKI system with a much larger ligand was found to behave differently from the other two systems with smaller ligands. In the former case, the intermolecular interactions are very favorable, and together with the favorable solvent-mediated intramolecular interactions, they overcome the large desolvation penalties to give a favorable electrostatics contribution to the overall binding affinity. On the other hand, the other two systems with smaller ligands only present modest intermolecular interactions and they are not or are only barely sufficient to overcome the desolvation penalty even with the aid of the favorable intramolecular contributions. As a result, the binding affinity of these two systems do not or only barely benefit from electrostatics contributions.


Acetylcholinesterase: Pivotal Roles of its Long Omega Loop (Cys69-Cys96) in Regulating Binding

Jennifer M. Bui and J. Andrew McCammon

Chemico-Biological Interactions, Vol. 157-158, pp. 357-359 (2005)

[PubMed: 16429484]

Modulation of synaptic activity is largely governed by the enzymatic activity of acetylcholinesterase (AChE), which rapidly catalyzes the hydrolysis of the neurotransmitter acetylcholine. One enigma that has drawn much attention is the very fast (diffusion-controlled) kinetics of the enzyme given that its catalytic triad is located at the bottom of a 20 Å deep and narrow gorge1,2. A large portion of the gorge is formed by a number of residues from the long omega loop (Cys69-Cys96 in mouse), and experimental studies3,4 have shown that conformational variations of this loop accompany ligand binding. A 15ns molecular dynamics simulation of mAChE in the presence of neurotoxin fasciculin-2 (FAS) is reported here and reveals a substantial increase in the magnitude of fluctuations for mAChE. In particular, the long omega loop is more flexible and its enhanced motions increase accessibility to the active site. A formation of a hydrophobic patch (Leu76-Phe80) by exposing its aromatic side chain to solvent surface, at the tip of this long omega loop is detected. This new discovery might provide not only a structural basis for interactions between a β-amyloid peptide and AChE, but also insights into the associations of AChE in Alzheimer's disease.


A gating mechanism proposed from a simulation of a human α7 nicotinic acetylcholine receptor

Richard J. Law, Richard H. Henchman and J. Andrew McCammon

Proceedings of the National Academy of Sciences of the USA, Vol. 102, No. 19, pp. 6813-6818 (2005)

[PubMed: 15857954]

The nicotinic acetylcholine receptor is a well characterized ligandgated ion channel, yet a proper description of the mechanisms involved in gating, opening, closing, ligand binding, and desensitization does not exist. Until recently, atomic-resolution structural information on the protein was limited, but with the production of the x-ray crystal structure of the Lymnea stagnalis acetylcholine binding protein and the EM image of the transmembrane domain of the torpedo electric ray nicotinic channel, we were provided with a window to examine the mechanism by which this channel operates. A 15-ns all-atom simulation of a homology model of the homomeric human α7 form of the receptor was conducted in a solvated palmitoyl-2-oleoyl-sn-glycerol-phosphatidylcholine bilayer and examined in detail. The receptor was unliganded. The structure undergoes a twist-to-close motion that correlates movements of the C loop in the ligand binding domain, via the β10-strand that connects the two, with the 10° rotation and inward movement of two nonadjacent subunits. The Cys loop appears to act as a stator around which the α-helical transmembrane domain can pivot and rotate relative to the rigid β-sheet binding domain. The M2-M3 loop may have a role in controlling the extent or kinetics of these relative movements. All of this motion, along with essential dynamics analysis, is suggestive of the direction of larger motions involved in gating of the channel.


Substrate concentration dependence of the diffusion-controlled steady-state rate constant

J. Dzubiella and J.A. McCammon

Journal of Chemical Physics, Vol. 122, Issue 18, article 184902, 7 pages (2005)

[PubMed: 15918760]

The Smoluchowski approach to diffusion-controlled reactions is generalized to interacting substrate particles by including the osmotic pressure and hydrodynamic interactions of the nonideal particles in the Smoluchoswki equation within a local-density approximation. By solving the strictly linearized equation for the time-independent case with absorbing boundary conditions, we present an analytic expression for the diffusion-limited steady-state rate constant for small substrate concentrations in terms of an effective second virial coefficient B2*. Comparisons to Brownian dynamics simulations excluding hydrodynamic interactions show excellent agreement up to bulk number densities of B2* ρ0 < 0.4 for hard sphere and repulsive Yukawa-like interactions between the substrates. Our study provides an alternative way to determine the second virial coefficient of interacting macromolecules experimentally by measuring their steady-state rate constant in diffusion-controlled reactions at low densities.


Pushing the limits: Editorial overview

J. Andrew McCammon and Rebecca C. Wade

Current Opinion in Structural Biology, Vol. 15, Issue 2, pp. 135-136 (2005)

Many of the contributions to the current section can be viewed as communications from various fronts in our drive to increase the realism of biomolecular simulations. Long-standing challenges have included bridging the gaps between the spatial and temporal scales of typical simulations (limited to tens of nanometers and tens of nanoseconds for many popular simulation methods) and the scales of physiological processes, which are often many orders of magnitudes larger. Other challenges have included making the energy functions that are used in typical simulations more accurate. This includes not only “tweaking” the parameters in molecular mechanics or other models, but also allowing for changes in the protonation state of biopolymers that may be coupled with their conformational changes. As will be seen, useful advances have been made recently in both directions. Adequate sampling of molecular configurations is particularly important in free energy simulations, and recent theoretical progress has provided valuable new computational tools for such simulations. Other contributions to the current section focus on advances in applications of biomolecular simulations. Progress in this area is leading to improved methods for understanding molecular recognition and the activity of aquaporins.


Optimized radii for Poisson-Boltzmann calculations with the AMBER force field

Jessica M.J. Swanson, Stewart A. Adcock and J. Andrew McCammon

Journal of Chemical Theory and Computation, Vol. 1, No. 3, pp. 484-493 (2005)

Implicit solvent models are a standard tool for assessing the electrostatics of biomolecular systems. The accuracy of quantitative predictions, such as pKa values, transfer free energies, binding energies, and solvation forces, is strongly dependent on one's choice of continuum parameters: the solute charges, dielectric coefficient, and radii, which define the dielectric boundary. To ensure quantitative accuracy, these parameters can be benchmarked against explicit solvent simulations. Here we present two sets of optimized radii to define either abrupt or cubic-spline smoothed dielectric boundaries in Poisson-Boltzmann calculations of protein systems with AMBER (parm99) charges. Spline smoothing stabilizes the electrostatic potential at the molecular surface, allowing for continuum force calculations. Most implementations, however, require significantly different radii than the abrupt boundary surfaces. The optimal continuum radii are initially approximated from the solvent radial charge distribution surrounding each atom type. A genetic algorithm is then used to fine-tune the starting values to reproduce charging free energies measured from explicit solvent simulations. The optimized radii are tested on four protein-like polypeptides. The results show increased accuracy of molecular solvation energies and atomic forces relative to commonly used continuum parameter sets. These radii are suitable for Poisson-Boltzmann calculations with the AMBER force field and offer energetic congruence to any model that combines molecular mechanics and Poisson-Boltzmann solvation energies.


Computation of electrostatic forces between solvated molecules determined by the Poisson-Boltzmann equation using a boundary element method

Benzhuo Lu, Deqiang Zhang and J. Andrew McCammon

Journal of Chemical Physics, Vol. 122, Issue 21, article 214102, 7 pages (2005)

[PubMed: 15974723]

A rigorous approach is proposed to calculate the electrostatic forces among an arbitrary number of solvated molecules in ionic solution determined by the linearized Poisson-Boltzmann equation. The variational principle is used and implemented in the frame of a boundary element method. This approach does not require the calculation of the Maxwell stress tensor on the molecular surface, therefore it totally avoids the hypersingularity problem in the direct BEM whenever one needs to calculate the gradient of the surface potential or the stress tensor. This method provides an accurate and efficient way to calculate the full inter-molecular electrostatic interaction energy and force, which could potentially be used in Brownian dynamics simulation of biomolecular association. The method has been tested on some simple cases to demonstrate its reliability and efficiency, and parts of the results are compared with analytical results and with those obtained by some known methods such as adaptive Poisson-Boltzmann solver.


The folding energy landscape and phosphorylation: modeling the conformational switch of the NFAT regulatory domain

Tongye Shen, Chenghang Zong, Donald Hamelberg, J. Andrew McCammon and Peter G. Wolynes

The FASEB Journal, Vol. 19, Issue 11, pp. 1389-1395 (2005)

[PubMed: 16126906]

An energy landscape approach predicts the conformational changes of the configurations of the regulatory domain of the protein nuclear factor of activated T cells (NFAT) caused by phosphorylation of specific multiple sites. Structurally local effects and secondary structural changes are modeled using all-atom Brownian dynamics to investigate the changes of the backbone torsional distributions upon phosphorylation. For tertiary and global changes, we employ a coarse-grained model to sample ensembles of conformations both with and without phosphorylation. At the secondary structure level, phosphorylation moderately increases the helical propensity and gives a more rigid local backbone conformation. The tertiary effects of phosphorylation caused by the extensive charge modification are more pronounced and collectively change the conformation of the regulatory domain of NFAT from a flexible globular ensemble to a rather rigid helical bundle, blocking access to the nuclear localization sequence. These studies give computational support to one scenario conjectured from experiments.


Relating kinetic rates and local energetic roughness by accelerated molecular dynamics simulations

Donald Hamelberg, Tongye Shen and J. Andrew McCammon

Journal of Chemical Physics, Vol. 122, Issue 24, article 241103, 4 pages (2005)

We show that our accelerated molecular dynamics (MD) approach can extend the time scale in all-atom MD simulations of biopolymers. We also show that this technique allows for kinetic rate information to be recaptured. In deducing the kinetic rates, the relationship between the local energetic roughness of the potential energy landscape and the effective diffusion coefficient is established. These are demostrated on a very slow but important biomolecular process: the dynamics of cis-trans isomerization of Ser-Pro motifs. We do not only recapture the slow kinetics rates, which is difficult in traditional MD; but also obtain the underlying roughness of the energy landscape of proteins at atomistic resolution.


Exploring Global Motions and Correlations in the Ribosome

Joanna Trylska, Valentina Tozzini and J. Andrew McCammon

Biophysical Journal, Vol. 89, No. 3, pp. 1455-1463 (2005)

[PubMed: 15951386]

We studied slower global coupled motions of the ribosome with half a microsecond of coarse-grained molecular dynamics. A low-resolution anharmonic network model that allows for the evolution of tertiary structure and long-scale sampling was developed and parameterized. Most importantly, we find that functionally important movements of L7/L12 and L1 lateral stalks are anticorrelated. Other principal directions of motions include widening of the tRNA cleft and the rotation of the small subunit which occurs as one block and is in phase with the movement of L1 stalk. The effect of the dynamical correlation pattern on the elongation process is discussed. Small fluctuations of the 3' tRNA termini and anticodon nucleotides show tight alignment of substrates for the reaction. Our model provides an efficient and reliable way to study the dynamics of large biomolecular systems composed of both proteins and nucleic acids.


A coarse grained model for the dynamics of the early stages of the binding mechanism of HIV-1 Protease

Valentina Tozzini and J. Andrew McCammon

Chemical Physics Letters, Vol. 413, Issue 1-3, pp. 123-128 (2005)

A coarse grained model for proteins is developed and applied to HIV-1 protease. Molecular dynamics simulations on the μsec timescale and the use of a flexible force field allow study of the opening of the "flaps" protecting the active site. The opening mechanism reveals peculiar features that might be involved in the substrate capture. An allosteric inhibition effect is demonstrated in specific regions of the protein. This study indicates alternative conformations and target sites to be used as basis for the design of novel inhibitor drugs.


Exploring Assembly Energetics of the 30S Ribosomal Subunit Using an Implicit Solvent Approach

Joanna Trylska, J. Andrew McCammon and Charles L. Brooks III

Journal of the American Chemical Society, Vol. 127, No. 31, pp. 11125-11133 (2005)

[PubMed: 16076220]

To explore the relationship between the assembly of the 30S ribosomal subunit and interactions among the constituent components, 16S RNA and proteins, relative binding free energies of the T. thermophilus 30S proteins to the 16S RNA were studied based on an implicit solvent model of electrostatic, nonpolar, and entropic contributions. The late binding proteins in our assembly map were found not to bind to the naked 16S RNA. The 5' domain early kinetic class proteins, on average, carry the highest positive charge, get buried the most upon binding to 16S RNA, and show the most favorable binding. Some proteins (S10/S14, S6/S18, S13/S19) have more stabilizing interactions while binding as dimers. Our computed assembly map resembles that of E. coli; however, the central domain path is more similar to that of A. aeolicus, a hyperthermophilic bacteria.


Molecular Docking of Balanol to Dynamics Snapshots of Protein Kinase A

Chung F. Wong, Jeremy Kua, Yingkai Zhang, T.P. Straatsma and J. Andrew McCammon

Proteins: Structure, Function, and Bioinformatics, Vol. 61, Issue 4, pp. 850-858 (2005)

[PubMed: 16245317]

Even if the structure of a receptor has been determined experimentally, it may not be a conformation to which a ligand would bind when induced fit effects are significant. Molecular docking using such a receptor structure may thus fail to recognize a ligand to which the receptor can bind with reasonable affinity. Here, we examine one way to alleviate this problem by using an ensemble of receptor conformations generated from a molecular dynamics simulation for molecular docking. Two molecular dynamics simulations were conducted to generate snapshots for protein kinase A: one with the ligand bound, the other without. The ligand, balanol, was then docked to conformations of the receptors presented by these trajectories. The Lamarckian genetic algorithm in Autodock ([Goodsell et al., J Mol Recognit 1996; 9(1):1-5]; [Morris et al., J Comput Chem 1998;19(14):1639-1662]) was used in the docking. Three ligand models were used: rigid, flexible, and flexible with torsional potentials. When the snapshots were taken from the molecular dynamics simulation of the protein-ligand complex, the correct docking structure could be recovered easily by the docking algorithm in all cases. This was an easier case for challenging the docking algorithm because, by using the structure of the protein in a protein-ligand complex, one essentially assumed that the protein already had a pocket to which the ligand can fit well. However, when the snapshots were taken from the ligand-free protein simulation, which is more useful for a practical application when the structure of the protein-ligand complex is not known, several clusters of structures were found. Of the 10 docking runs for each snapshot, at least one structure was close to the correctly docked structure when the flexible-ligand models were used. We found that a useful way to identify the correctly docked structure was to locate the structure that appeared most frequently as the lowest energy structure in the docking experiments to different snapshots.


The Entropic Cost of Protein-Protein Association: A Case Study on Acetylcholinesterase Binding to Fasciculin-2

David D.L. Minh, Jennifer M. Bui, Chia-en Chang, Tushar Jain, Jessica M.J. Swanson and J. Andrew McCammon

Biophysical Journal, Vol. 89, No. 4, pp. L25-L27 (2005)

[PubMed: 16100267]

Protein-protein association is accompanied by a large reduction in translational and rotational (external) entropy. Based on a 15 ns molecular dynamics simulation of acetylcholinesterase (AChE) in complex with fasciculin 2 (Fas2), we estimate the loss in external entropy using quasiharmonic analysis and histogram-based approximations of the probability distribution function. The external entropy loss of AChE-Fas2 binding, ~30 cal/mol K, is found to be significantly larger than most previously characterized protein-ligand systems. However, it is less than the entropy loss estimated in an earlier study by A.V. Finkelstein and J. Janin, which was based on atomic motions in crystals.

In Table 1 and 2, labels for translational and rotational degrees of freedom are switched. Similarly, the sentence above figure 2, which reads "the rotational entropy of the complex" should be "the translational entropy of the complex." The end of the following paragraph, which reads "artifactual motions in rotational phase space" should be "artifactual motions in translational phase space."


Limitations of Atom-Centered Dielectric Functions in Implicit Solvent Models

Jessica M.J. Swanson, John Mongan and J. Andrew McCammon

Journal of Physical Chemistry B, Vol. 109, No. 31, pp. 14769-14772 (2005)

[PubMed: 16852866]

Many recent advances in Poisson-Boltzmann and generalized Born implicit solvent models have used atom-centered polynomial or Gaussian functions to define the boundary separating low and high dielectric regions. In contrast to the Lee and Richards molecular surface, atom-centered surfaces result in interatomic crevices and buried pockets of high dielectric which are too small for a solvent molecule to occupy. We show that these interstitial high dielectric regions are of significant magnitude in globular proteins, that they artificially increase solvation energies, and that they distort the free energy surface of nonbonded interactions. These results suggest that implicit solvent dielectric functions must exclude interstitial high dielectric regions in order to yield physically meaningful results.


Calculation of the Maxwell stress tensor and the Poisson-Boltzmann force on a solvated molecular surface using hypersingular boundary integrals

Benzhuo Lu, Xiaolin Cheng, Tingjun Hou and J. Andrew McCammon

Journal of Chemical Physics, Vol. 123, Issue 8, article 084904, 8 pages (2005)

[PubMed: 16164327]

The electrostatic interaction among molecules solvated in ionic solution is governed by the Poisson-Boltzmann equation (PBE). Here the hypersingular integral technique is used in a boundary element method (BEM) for the three-dimensional (3D) linear PBE to calculate the Maxwell stress tensor on the solvated molecular surface, and then the PB forces and torques can be obtained from the stress tensor. Compared with the variational method (also in a BEM frame) that we proposed recently, this method provides an even more efficient way to calculate the full intermolecular electrostatic interaction force, especially for macromolecular systems. Thus, it may be more suitable for the application of Brownian dynamics methods to study the dynamics of protein/protein docking as well as the assembly of large 3D architectures involving many diffusing subunits. The method has been tested on two simple cases to demonstrate its reliability and efficiency, and also compared with our previous variational method used in BEM.


Target Flexibility in Molecular Recognition

J. Andrew McCammon

Biochimica et Biophysica Acta, Vol. 1754, Issue 1-2, pp. 221-224 (2005, Special issue on Inhibitors of Protein Kinases)

[PubMed: 16181817]

Induced-fit effects are well known in the binding of small molecules to proteins and other macromolecular targets. Among other targets, protein kinases are particularly flexible proteins, so that such effects should be considered in attempts at structure-based inhibitor design for kinase targets. This paper outlines some recent progress in methods for including target flexibility in computational studies of molecular recognition. A focus is the "relaxed complex method," in which ligands are docked to an ensemble of conformations of the target, and the best complexes are re-scored to provide predictions of optimal binding geometries. Early applications of this method have suggested a new approach to the development of inhibitors of HIV-1 Integrase.


Fast Peptidyl cis-trans Isomerization within the Flexible Gly-Rich Flaps of HIV-1 Protease

Donald Hamelberg and J. Andrew McCammon

Journal of the American Chemical Society, Vol. 127, No. 40, pp. 13778-13779 (2005)

[PubMed: 16201784]

The catalytic aspartyl protease of the HIV-1 virus is a homodimer with two flaps that control access to the active site and are known to be flexible. However, knowledge of the atomistic mechanism of the flexibility is lacking. We show that the Gly-Gly -bond in the glycine-rich flap tips undergoes fast cis-trans isomerization on the microsecond to millisecond time scale rather than in the usual seconds. Further study reveals that the unexpectedly fast isomerization is a direct consequence of the -hairpin loop structure of the flap tips, which appears to be counterintuitive. After loop formation of a linear peptide containing the Gly-Gly motif, the rate of isomerization is shown to increase by many orders of magnitude.


Potent, Selective Pyrone-Based Inhibitors of Stromelysin-1

David T. Puerta, John Mongan, Ba L. Tran, J. Andrew McCammon and Seth M. Cohen

Journal of the American Chemical Society, Vol. 127, No. 41, pp. 14148-14149 (2005)

[PubMed: 16218585]

In an effort to develop alternatives to hydroxamate-based matrix metalloproteinase inhibitors (MPIs), we have utilized the drug discovery program LUDI enhanced with the structural coordinates of a bioinorganic model complex. This method has yielded the first pyrone-based MPIs. The inhibitors demonstrate nanomolar potency against MMP-3 and are selective for MMP-3 over MMP-2 and MMP-1. We postulate that the potency and unusual selectivity profile of these MPI is attributable to the pyrone chelating group.


Induced Fit in Mouse Acetylcholinesterase upon Binding a Femtomolar Inhibitor: A Molecular Dynamics Study

Sanjib Senapati, Jennifer M. Bui and J. Andrew McCammon

Journal of Medicinal Chemistry, Vol. 48, No. 26, pp. 8155-8162 (2005)

[PubMed: 16366597]

A molecular dynamics simulation of mouse acetylcholinesterase (mAChE) complexed with syn-TZ2PA6, a femtomolar AChE inhibitor, is compared to a simulation of unliganded mAChE. The simulation of the complex was initiated by placing the inhibitor in its bound conformation of the crystal complex into a structure of unliganded mAChE selected from preliminary protein-ligand docking results. During a 2 ns period, the enzyme subsequently displayed a substantial "induced fit" response to yield a conformation very similar to that obtained by crystallography (Bourne et al. Proc. Natl. Acad. Sci. USA 2004, 101, 1449-1454). In this conformation of unique nature, the Trp 286 side chain of the enzyme flips out of the hydrophobic core and becomes highly solvent exposed. The imidazole ring of His 287 is almost orthogonal relative to its position in the unliganded enzyme, creating a stable π stacking arrangement with the Trp 286 side chain. Other major deviations among the active site residues include side chain conformational changes of Trp 86, Tyr 133, Tyr 337, and Phe 338. These residues in the complex deviate from their positions in unliganded mAChE to better accommodate the inhibitor in the active site gorge.


The Association of Tetrameric Acetylcholinesterase with ColQ Tail: A Block Normal Mode Analysis

Deqiang Zhang and J. Andrew McCammon

PLoS Computational Biology, Vol. 1, Issue 6, pp. 484-491 (2005)

[PubMed: 16299589]

Acetylcholinesterase (AChE) rapidly hydrolyzes acetylcholine in the neuromuscular junctions and other cholinergic synapses to terminate the neuronal signal. In physiological conditions, AChE exists as tetramers associated with the proline-rich attachment domain (PRAD) of either collagen-like Q subunit (ColQ) or proline-rich membrane-anchoring protein. Crystallographic studies have revealed that different tetramer forms may be present, and it is not clear whether one or both are relevant under physiological conditions. Recently, the crystal structure of the tryptophan amphiphilic tetramerization (WAT) domain of AChE associated with PRAD ([WAT]4PRAD), which mimics the interface between ColQ and AChE tetramer, became available. In this study we built a complete tetrameric mouse [AChET]4-ColQ atomic structure model, based on the crystal structure of the [WAT]4PRAD complex. The structure was optimized using energy minimization. Block normal mode analysis was done to investigate the low-frequency motions of the complex and to correlate the structure model with the two known crystal structures of AChE tetramer. Significant low-frequency motions among the catalytic domains of the four AChE subunits were observed, while the [WAT]4PRAD part held the complex together. Normal mode involvement analysis revealed that the two lowest frequency modes were primarily involved in the conformational changes leading to the two crystal structures. The first 30 normal modes can account for more than 75% of the conformational changes in both cases. The evidence further supports the idea of a flexible tetramer model for AChE. This model can be used to study the implications of the association of AChE with ColQ.


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