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Thermodynamics of Enzyme Folding and Activity: Theory and Experiment
C.F. Wong and J.A. McCammon
In "Structure, Dynamics and Function of Biomolecules," A. Ehrenberg and R. Rigler, Eds., Springer-Verlag, Berlin, pp. 51-55 (1987)
Physics Today, Vol. 40, pp. S12-S13 (1987)
Sidechain Rotational Isomerization in Proteins: Dynamic Simulation with Solvent Surroundings
Indira Ghosh and J. Andrew McCammon
Molecular dynamics simulations are used to study the rotational isomerization of the tyrosine 35 ring in bovine pancreatic trypsin inhibitor immersed in liquid water. Inclusion of the solvent surroundings improves the agreement with experimental results significantly, although the theoretical free energy barrier (13 kcal/mol at 300K) is still approximately 3 kcal/mol below that found by nuclear magnetic resonance studies. This remaining discrepancy will probably be eliminated in future calculations by the use of a more accurate model for the hydrogen atoms on the tyrosine ring. An important finding in the present work is that frictional effects due to solvent damping appear to be small for the tyrosine 35 ring, which is largely but not completely buried in the protein surface.
Solvent Viscosity Effects on the Rate of Side-Chain Rotational Isomerization in a Protein Molecule
Indira Ghosh and J. Andrew McCammon
The activated rotation of the tyrosine 35 ring in bovine pancreatic trypsin inhibitor has been simulated in model solvents that have extremely different viscosities but that are otherwise identical. Both simulations are at 300 K, but one solvent corresponds to liquid water and the other to a hypothetical glassy water. Although the ring is located in the surface region of the protein, the "freezing" of the solvent reduces the rate constant for rotation by only 50%. The time required to complete individual transitions is somewhat lengthened, apparently due to slowed relaxation both of ring-solvent interactions and of the conformation of the protein matrix that surrounds most of the ring. The slowing of these relaxations also leads to the reduction in the rate constant: the persistence of ring environments that favor rotation increases the likelihood that the ring will return to the transition-state region soon after passing through it, rather than being trapped in a stable state.
Trajectory Simulation Studies of Diffusion-Controlled Reactions
J. Andrew McCammon, Russell J. Bacquet, Stuart A. Allison and Scott H. Northrup
Computer simulations of the Brownian trajectories of reactant molecules in solution can be used to calculate the rates of diffusion-controlled reactions. This paper presents new derivations of some of the basic equations used in such calculations and the results of applications to two problems from biology.
Molecular Dynamics Studies on Antiviral Agents: Thermodynamics of Solvation and Binding
T.P. Lybrand, W.F. Lau, J.A. McCammon and B.M. Pettitt
In "Protein Structure and Design," UCLA Symposia on Molecular and Cellular Biology, New Series, Volume 69, D. Oxender, Ed., Alan R. Liss, Inc., New York, pp. 227-233 (1987)
Electrophoretic Light Scattering from Macromolecular Solutions and Conformational Dynamics
J.B. Hubbard and J.A. McCammon
We propose a theory for the influence of conformational dynamics of solvated macromolecules on the translational self-correlation functions and associated laser light scattering spectra of the solution in an external electric field. This theory assumes that the electrophoretic drift velocity of a macroion may be coupled to its internal degrees of freedom via an unspecified auxiliary stochastic process to which we refer as "electrophoretic mobility fluctuations". A surprisingly diverse set of fluctuation-generated spectral signatures, which depend strongly on the underlying statistical model, emerge from the analysis. These effects range from skewed Lorentzian profiles to satellite lines having a field-dependent amplitude.
Computer-Aided Molecular Design
J. Andrew McCammon
Theoretical chemistry, as implemented on fast computers, is beginning to yield accurate predictions of the thermodynamic and kinetic properties of large molecular assemblies. In addition to providing detailed insights into the origins of molecular activity, theoretical calculations can be used to design new molecules with specific properties. This article describes two types of calculations that show special promise as design tools, the thermodynamic cycle-perturbation method and the Brownian reactive dynamics method. These methods can be applied to calculate equilibrium and rate constants that describe many aspects of molecular recognition, stability, and reactivity.
Geometric Considerations in the Calculation of Relative Free Energies of Activation
Jeffry D. Madura, B. Montgomery Pettitt and J. Andrew McCammon
A method that locates transition state structures between homologous reactions and, with the use of the thermodynamic cycle-perturbation technique, determines the relative free energy of activation between the transition states is presented. A simple model system which displays the problem of finding condensed phase transition states is used to illustrate the method.
Simulation of the Diffusion-Controlled Reaction Between Superoxide and Superoxide Dismutase. II. Detailed Models
S.A. Allison, R.J. Bacquet and J.A. McCammon
A two-stage Brownian dynamics simulation method is used to study the diffusion-influenced bimolecular reaction between superoxide and superoxide dismutase (SOD). The crystal structure of the dimeric enzyme is used in constructing detailed topographical and electrostatic models. Several electrostatic models are considered. In the most realistic, the excluded volume of the protein, which is impermeable to penetration by mobile ions, is assigned a dielectric constant of 2 and the surrounding "solvent" is assigned a value of 78. A finite difference method is used to solve the linearized Poisson-Boltzmann equation. For native SOD, the simulations reproduce the pronounced salt dependence of the rate constant observed experimentally. This salt dependence is attributed to electrostatic interactions between enzyme and substrate that are inherently attractive and amplified by the low dielectric constant of the protein interior. The simulation method is also applied to a modified enzyme, acylated SOD.
Symposium Overview. Minnesota Conference on Supercomputing in Biology: Proteins, Nucleic Acids, and Water
George L. Wilcox, Florante A. Quiocho, Cyrus Levinthal, Stephen C. Harvey, Gerald M. Maggiora and J. Andrew McCammon
This was the first academically organized conference dealing exclusively with biological applications of supercomputers. The symposium was organized to explore in a systematic way the current state of the art in application of large scale computation to problems in physical biochemistry. The conference was held September 13-16, 1987 on the campus of the University of Minnesota in Minneapolis, Minnesota. Primary support was provided by the Minnesota Supercomputer Institute; other support came from other divisions of the University and from several corporations. Total attendance was over 140, including 24 speakers and session chairpersons.
Quantum Simulation of Ferrocytochrome c
Chong Zheng, Chung F. Wong, J. Andrew McCammon and Peter G. Wolynes
The dramatic progress in the understanding of the dynamics of biomolecules has been largely fuelled by computer simulations based on the law of classical mechanics. However in some respects biomolecules are at the borders of the domain of applicability of classical mechanics. The role of quantum mechanical effects in biomolecular structure and function is therefore worth investigating. Here we present preliminary results from a quantum simulation of a protein and contrast them with results from full classical simulations. The most significant differences are found in motions of high frequency, such as bond stretching or the torsional oscillation of groups that bear hydrogen atoms. The amplitudes of such motions are significantly increased by the penetration of atoms into classically forbidden regions. These differences will directly influence the rates of such processes as proton and electron transfer.
Ionic Strength Dependence of Enzyme-Substrate Interactions. Monte Carlo and Poisson-Boltzmann Results for Superoxide Dismutase
Russell J. Bacquet, J. Andrew McCammon and Stuart A. Allison
Monte Carlo (MC) simulations have been carried out for simplified models of the enzyme superoxide dismutase at infinite dilution in several aqueous salt solutions. Comparison is made to results obtained from numerical algorithms based on Poisson-Boltzmann (PB) theory. The impact of approximations inherent in the PB approach is found to be small. The diffusion-limited rate constant for enzyme-substrate association is computed from the MC data. The results are qualitatively in accord with experimental data. Better agreement can be obtained by using more detailed models, but this requires the use of PB rather than MC due to computational requirements. The major conclusion of this study is therefore that the approximations inherent in the PB theory are acceptable in the present application.
Computer Simulation of Proteins: Classical and Quantum Dynamics
C.F. Wong and J.A. McCammon
In "Science at the John von Neumann Center, 1987," L. Anacker, Ed., John von Neumann Center, Princeton University, pp. 131-134 (1988)
Supercomputer Simulation and Biomolecular Design
J.A. McCammon, G. Ganti, T.P. Lybrand and C.F. Wong
In "High Speed Computing, Scientific Applications and Algorithm Design," R.B. Wilhelmson, Ed., University of Illinois Press, pp. 155-161 (1988)
Molecular Dynamics Simulation Studies of Water and Protein Solutions
C.F. Wong and J.A. McCammon
In "Science on the ETA10," L. Anacker, Ed., John Von Neumann Center, Princeton University, pp. 72-77 (1988)