Free energy simulations: The meaning of the individual contributions from a component analysis
- 1 September 1994
- journal article
- research article
- Published by Wiley in Proteins-Structure Function and Bioinformatics
- Vol. 20 (1), 25-33
- https://doi.org/10.1002/prot.340200105
Abstract
A theoretical analysis is made of the decomposition into contributions from individual interactions of the free energy calculated by thermodynamic integration. It is demonstrated that such a decomposition, often referred to as “component analysis,” is meaningful, even though it is a function of the integration path. Moreover, it is shown that the path dependence can be used to determine the relation of the contribution of a given interaction to the state of the system. To illustrate these conclusions, a simple transformation(Cl− to Br− in aqueous solution) is analyzed by use of the Reference Interaction Site Model-Hypernetted Chain Closure integral equation approach; it avoids the calculational difficulties of macromolecular simulation while retaining their conceptual complexity. The difference in the solvation free energy between chloride and bromide is calculated, and the contributions of the Lennard-Jones and electrostatic terms in the potential function are analyzed by the use of suitably chosen integration paths. The model is also used to examine the path dependence of individual contributions to the double free energy differences (ΔΔG or ΔΔA) that are often employed in free energy simulations of biological systems. The alchemical path, as contrasted with the experimental path, is shown to be appropriate for interpreting the effects of mutations on ligand binding and protein stability. The formulation is used to obtain a better understanding of the success of the Poisson-Boltzmann continuum approach for determining the solvation properties of polar and ionic systems.Keywords
This publication has 39 references indexed in Scilit:
- Molecular recognition in proteinsJournal of Molecular Biology, 1994
- Free energy calculations: Applications to chemical and biochemical phenomenaChemical Reviews, 1993
- Computational AlchemyAnnual Review of Physical Chemistry, 1992
- Precision of free energies calculated by molecular dynamics simulations of peptides in solutionJournal of Computational Chemistry, 1992
- Free energy perturbation study on a Trp-binding mutant (Ser88 →Cys) of the trp-repressorProtein Engineering, Design and Selection, 1992
- Contribution of the hydrophobic effect to protein stability: analysis based on simulations of the Ile-96----Ala mutation in barnase.Proceedings of the National Academy of Sciences, 1991
- Simulation analysis of the stability mutant R96H of T4 lysozymeBiochemistry, 1991
- Free energy calculations on protein stability: Thr-157 .fwdarw. Val-157 mutation of T4 lysozymeJournal of the American Chemical Society, 1989
- Advances in Chemical PhysicsAdvances in Chemical Physics, 1988
- Optimized intermolecular potential functions for amides and peptides. Structure and properties of liquid amidesJournal of the American Chemical Society, 1985