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Is the prediction of p K a values by constant‐pH molecular dynamics being hindered by inherited problems?
Author(s) -
Machuqueiro Miguel,
Baptista António M.
Publication year - 2011
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.23115
Subject(s) - molecular dynamics , nanosecond , force field (fiction) , constant (computer programming) , lysozyme , boltzmann constant , chemistry , value (mathematics) , field (mathematics) , yield (engineering) , statistical physics , thermodynamics , physics , biological system , computational chemistry , mathematics , computer science , statistics , laser , biochemistry , quantum mechanics , biology , pure mathematics , programming language , optics
In this study, we investigate two factors that can hinder the performance of constant‐pH molecular dynamics methods in predicting protein p K a values, using hen egg white lysozyme as a test system. The first factor is related to the molecular definition and p K a value of model compounds in the Poisson‐Boltzmann framework. We address this by defining the model compound as a molecular fragment with an associated p K a value that is calibrated against experimental data, which results in a decrease of 0.12 units in p K a errors. The second addressed factor is the possibility that detrimental structural distortions are being introduced in the simulations by the underlying molecular mechanics force field. This issue is investigated by analyzing how the gradual structural rearrangements affect the predicted p K a values. The two GROMOS force fields studied here (43A1 and 53A6) yield good p K a predictions, although a time‐dependent performance is observed: 43A1 performs better after a few nanoseconds of structural reorganization (p K a errors of ∼0.45), while 53A6 gives the best prediction right at the first nanosecond (p K a errors of 0.42). These results suggest that the good performance of constant‐pH molecular dynamics methods could be further improved if these force field limitations were overcome. Proteins 2011;. © 2011 Wiley‐Liss, Inc.