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Calculation of protein ionization equilibria with conformational sampling: pK a of a model leucine zipper, GCN4 and barnase
Author(s) -
Gorfe Alemayehu A.,
Ferrara Philippe,
Caflisch Amedeo,
Marti Daniel N.,
Bosshard Hans Rudolf,
Jelesarov Ilian
Publication year - 2001
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.10027
Subject(s) - barnase , leucine zipper , conformational ensembles , chemistry , molecular dynamics , context (archaeology) , zipper , biological system , sampling (signal processing) , computational chemistry , statistical physics , physics , mathematics , algorithm , biochemistry , ribonuclease , paleontology , rna , biology , peptide sequence , gene , detector , optics
The use of conformational ensembles provided by nuclear magnetic resonance (NMR) experiments or generated by molecular dynamics (MD) simulations has been regarded as a useful approach to account for protein motions in the context of pK a calculations, yet the idea has been tested occasionally. This is the first report of systematic comparison of pK a estimates computed from long multiple MD simulations and NMR ensembles. As model systems, a synthetic leucine zipper, the naturally occurring coiled coil GCN4, and barnase were used. A variety of conformational averaging and titration curve‐averaging techniques, or combination thereof, was adopted and/or modified to investigate the effect of extensive global conformational sampling on the accuracy of pK a calculations. Clustering of coordinates is proposed as an approach to reduce the vast diversity of MD ensembles to a few structures representative of the average electrostatic properties of the system in solution. Remarkable improvement of the accuracy of pK a predictions was achieved by the use of multiple MD simulations. By using multiple trajectories the absolute error in pK a predictions for the model leucine zipper was reduced to as low as approximately 0.25 pK a units. The validity, advantages, and limitations of explicit conformational sampling by MD, compared with the use of an average structure and a high internal protein dielectric value as means to improve the accuracy of pK a calculations, are discussed. Proteins 2002;46:41–60. © 2001 Wiley‐Liss, Inc.