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Diffusive reaction dynamics on invariant free energy profiles.

ABSTRACT: A fundamental problem in the analysis of protein folding and other complex reactions in which the entropy plays an important role is the determination of the activation free energy from experimental measurements or computer simulations. This article shows how to combine minimum-cut-based free energy profiles (F(C)), obtained from equilibrium molecular dynamics simulations, with conventional histogram-based free energy profiles (F(H)) to extract the coordinate-dependent diffusion coefficient on the F(C) (i.e., the method determines free energies and a diffusive preexponential factor along an appropriate reaction coordinate). The F(C), in contrast to the F(H), is shown to be invariant with respect to arbitrary transformations of the reaction coordinate, which makes possible partition of configuration space into basins in an invariant way. A "natural coordinate," for which F(H) and F(C) differ by a multiplicative constant (constant diffusion coefficient), is introduced. The approach is illustrated by a model one-dimensional system, the alanine dipeptide, and the folding reaction of a double beta-hairpin miniprotein. It is shown how the results can be used to test whether the putative reaction coordinate is a good reaction coordinate.

SUBMITTER: Krivov SV

PROVIDER: S-EPMC2544541 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Diffusive reaction dynamics on invariant free energy profiles.

Krivov Sergei V SV Karplus Martin M

Proceedings of the National Academy of Sciences of the United States of America 20080904 37

A fundamental problem in the analysis of protein folding and other complex reactions in which the entropy plays an important role is the determination of the activation free energy from experimental measurements or computer simulations. This article shows how to combine minimum-cut-based free energy profiles (F(C)), obtained from equilibrium molecular dynamics simulations, with conventional histogram-based free energy profiles (F(H)) to extract the coordinate-dependent diffusion coefficient on t ...[more]

PMID: 18772379

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Project description:The calculations of potential of mean force along complex chemical reactions or rare events pathways are of great interest because of their importance for many areas in chemistry, molecular biology, and material science. The major difficulty for free energy calculations comes from the great computational cost for adequate sampling of the system in high-energy regions, especially close to the reaction transition state. Here, we present a method, called FEG-RBD, in which the free energy gradients were obtained from rigid body dynamics simulations. Then the free energy gradients were integrated along a reference reaction pathway to calculate free energy profiles. In a given system, the reaction coordinates defining a subset of atoms (e.g., a solute, or the quantum mechanics (QM) region of a quantum mechanics/molecular mechanics simulation) are selected to form a rigid body during the simulation. The first-order derivatives (gradients) of the free energy with respect to the reaction coordinates are obtained through the integration of constraint forces within the rigid body. Each structure along the reference reaction path is separately subjected to such a rigid body simulation. The individual free energy gradients are integrated along the reference pathway to obtain the free energy profile. Test cases provided demonstrate both the strengths and weaknesses of the FEG-RBD method. The most significant benefit of this method comes from the fast convergence rate of the free energy gradient using rigid-body constraints instead of restraints. A correction to the free energy due to approximate relaxation of the rigid-body constraint is estimated and discussed. A comparison with umbrella sampling using a simple test case revealed the improved sampling efficiency of FEG-RBD by a factor of 4 on average. The enhanced efficiency makes this method effective for calculating the free energy of complex chemical reactions when the reaction coordinate can be unambiguously defined by a small subset of atoms within the system.

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Diffusive reaction dynamics on invariant free energy profiles.

Publications

Diffusive reaction dynamics on invariant free energy profiles.

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