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Acidic range titration of HEWL using a constant‐pH molecular dynamics method
Author(s) -
Machuqueiro Miguel,
Baptista António M.
Publication year - 2008
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.21923
Subject(s) - chemistry , titration , molecular dynamics , denaturation (fissile materials) , dielectric , electrostatics , equilibrium constant , crystallography , thermodynamics , computational chemistry , analytical chemistry (journal) , chromatography , nuclear chemistry , materials science , physics , optoelectronics
In this work, we present the first application to a protein of the stochastic constant‐pH molecular dynamics (MD) method with the inclusion of proton tautomerism. The acidic titration of HEWL was performed under different conditions. Both generalized reaction field (GRF) and particle mesh Ewald (PME) methods were used in the treatment of the long range electrostatics and, even though the PME simulations revealed to be more stable, the better results were obtained using GRF (pK a RMSD of 0.82 for GRF and 1.13 for PME). The results using PME at different dielectric constants (2, 4, and 8) also revealed that there was no significant improvement in pK a 's prediction upon increasing the dielectric constant. The secondary structure analysis of HEWL revealed a remarkably stable protein in the acidic pH range. The β‐sheet strands (unlike the α‐helices) seem to be destabilized upon pH decrease, suggesting that the β‐domain is less stable than the α‐domain. The four principal α‐helices were also ordered according to their stability in the acidic pH range and the results (4 < 1 < 2 ≈ 3) were consistent with the ones obtained in thermal denaturation studies. Proteins 2008. © 2008 Wiley‐Liss, Inc.