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Improving the accuracy of protein pK a calculations: Conformational averaging versus the average structure
Author(s) -
van Vlijmen Herman W.T.,
Schaefer Michael,
Karplus Martin
Publication year - 1998
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/(sici)1097-0134(19981101)33:2<145::aid-prot1>3.0.co;2-i
Subject(s) - chemistry , titration curve , solvation , electrostatics , titration , work (physics) , molecular dynamics , lysozyme , ewald summation , computational chemistry , thermodynamics , solvent , physics , biochemistry , organic chemistry
Several methods for including the conformational flexibility of proteins in the calculation of titration curves are compared. The methods use the linearized Poisson‐Boltzmann equation to calculate the electrostatic free energies of solvation and are applied to bovine pancreatic trypsin inhibitor (BPTI) and hen egg‐white lysozyme (HEWL). An ensemble of conformations is generated by a molecular dynamics simulation of the proteins with explicit solvent. The average titration curve of the ensemble is calculated in three different ways: an average structure is used for the pK a calculation; the electrostatic interaction free energies are averaged and used for the pK a calculation; and the titration curve for each structure is calculated and the curves are averaged. The three averaging methods give very similar results and improve the pK a values to approximately the same degree. This suggests, in contrast to implications from other work, that the observed improvement of pK a values in the present studies is due not to averaging over an ensemble of structures, but rather to the generation of a single properly averaged structure for the pK a calculation. Proteins 33:145–158, 1998. © 1998 Wiley‐Liss, Inc.