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Is the prediction of pKa values by constant-pH molecular dynamics being hindered by inherited problems?

Authors

  • Miguel Machuqueiro,

    1. Centro de Química e Bioquímica, Faculdade de Ciências da Universidade de Lisboa, Campo Grande, C8, 1749-016 Lisboa, Portugal
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  • António M. Baptista

    Corresponding author
    1. Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Av. da República, EAN, 2780-157 Oeiras, Portugal
    • Instituto de Tecnologia Química e Biológica, Av. da República, EAN, 2780-157 Oeiras, Portugal
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  • The authors state no conflict of interest.

Abstract

In this study, we investigate two factors that can hinder the performance of constant-pH molecular dynamics methods in predicting protein pKa values, using hen egg white lysozyme as a test system. The first factor is related to the molecular definition and pKa value of model compounds in the Poisson-Boltzmann framework. We address this by defining the model compound as a molecular fragment with an associated pKa value that is calibrated against experimental data, which results in a decrease of 0.12 units in pKa 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 pKa values. The two GROMOS force fields studied here (43A1 and 53A6) yield good pKa predictions, although a time-dependent performance is observed: 43A1 performs better after a few nanoseconds of structural reorganization (pKa errors of ∼0.45), while 53A6 gives the best prediction right at the first nanosecond (pKa 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.

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