Thermodynamics of Enzyme Folding and Activity: Theory and ExperimentIn "Structure, Dynamics and Function of Biomolecules," A. Ehrenberg and R. Rigler, Eds., Springer-Verlag, Berlin, pp. 51-55 (1987) Molecular RecognitionPhysics Today, Vol. 40, pp. S12-S13 (1987) Sidechain Rotational Isomerization in Proteins: Dynamic Simulation with Solvent SurroundingsBiophysical Journal, Vol. 51, No. 4, pp. 637-641 (1987) [PubMed 3580489]
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 MoleculeJournal of Physical Chemistry, Vol. 91, No. 19, pp. 4878-4881 (1987)
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 ReactionsFaraday Discussions of the Chemical Society, Vol. 83, pp. 213-222 (1987) [PubMed 3440490]
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 BindingIn "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 DynamicsJournal of Chemical Physics, Vol. 87, Issue 8, pp. 4339-4343 (1987)
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 DesignScience, Vol. 238, No. 4826, pp. 486-491 (1987, Invited article) [PubMed 3310236]
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 ActivationChemical Physics Letters, Vol. 141, Issues 1-2, pp. 83-87 (1987)
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.