Premium
Absolute free energies of biomolecules from unperturbed ensembles
Author(s) -
Grigoryan Gevorg
Publication year - 2013
Publication title -
journal of computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.907
H-Index - 188
eISSN - 1096-987X
pISSN - 0192-8651
DOI - 10.1002/jcc.23448
Subject(s) - macromolecule , solvation , force field (fiction) , molecular dynamics , biomolecule , protein design , sequence (biology) , chemistry , protein folding , mean absolute error , folding (dsp implementation) , statistical physics , metric (unit) , conformational ensembles , computational chemistry , protein structure , physics , molecule , mathematics , quantum mechanics , biochemistry , statistics , organic chemistry , operations management , mean squared error , electrical engineering , economics , engineering
Computing the absolute free energy of a macromolecule's structural state, F , is a challenging problem of high relevance. This study presents a method that computes F using only information from an unperturbed simulation of the macromolecule in the relevant conformational state, ensemble, and environment. Absolute free energies produced by this method, dubbed V aluation of L ocal C onfiguration I ntegral with D ynamics (VALOCIDY), enable comparison of alternative states. For example, comparing explicitly solvated and vaporous states of amino acid side‐chain analogs produces solvation free energies in good agreement with experiments. Also, comparisons between alternative conformational states of model heptapeptides (including the unfolded state) produce free energy differences in agreement with data from μs molecular‐dynamics simulations and experimental propensities. The potential of using VALOCIDY in computational protein design is explored via a small design problem of stabilizing a β‐turn structure. When VALOCIDY‐based estimation of folding free energy is used as the design metric, the resulting sequence folds into the desired structure within the atomistic force field used in design. The VALOCIDY‐based approach also recognizes the distinct status of the native sequence regardless of minor details of the starting template structure, in stark contrast with a traditional fixed‐backbone approach. © 2013 Wiley Periodicals, Inc.