Constant pH molecular dynamics with proton tautomerism.

Abstract:

:The current article describes a new two-dimensional lambda-dynamics method to include proton tautomerism in continuous constant pH molecular dynamics (CPHMD) simulations. The two-dimensional lambda-dynamics framework is used to devise a tautomeric state titration model for the CPHMD simulations involving carboxyl and histidine residues. Combined with the GBSW implicit solvent model, the new method is tested on titration simulations of blocked histidine and aspartic acid as well as two benchmark proteins, turkey ovomucoid third domain (OMTKY3) and ribonuclease A (RNase A). A detailed analysis of the errors inherent to the CPHMD methodology as well as those due to the underlying solvation model is given. The average absolute error for the computed pKa values in OMTKY3 is 1.0 pK unit. In RNase A the average absolute errors for the carboxyl and histidine residues are 1.6 and 0.6 pK units, respectively. In contrast to the previous work, the new model predicts the correct sign for all the pKa shifts, but one, in the benchmark proteins. The predictions of the tautomeric states of His12 and His48 and the conformational states of His48 and His119 are in agreement with experiment. Based on the simulations of OMTKY3 and RNase A, the current work has demonstrated the capability of the CPHMD technique in revealing pH-coupled conformational dynamics of protein side chains.

journal_name

Biophys J

journal_title

Biophysical journal

authors

Khandogin J,Brooks CL 3rd

doi

10.1529/biophysj.105.061341

subject

Has Abstract

pub_date

2005-07-01 00:00:00

pages

141-57

issue

1

eissn

0006-3495

issn

1542-0086

pii

S0006-3495(05)72666-7

journal_volume

89

pub_type

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