Format

Send to

Choose Destination
Biophys J. 2005 Jul;89(1):141-57. Epub 2005 Apr 29.

Constant pH molecular dynamics with proton tautomerism.

Author information

1
Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA. janakhan@scripps.edu

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.

PMID:
15863480
PMCID:
PMC1366513
DOI:
10.1529/biophysj.105.061341
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center