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Constant pH Molecular Dynamics with Proton Tautomerism

Department of Molecular Biology, The Scripps Research Institute, La Jolla, California

Correspondence: Address reprint requests to Jana Khandogin, Tel.: 858-784-8070; Fax: 858-784-8688; E-mail: janakhan{at}scripps.edu.

The current article describes a new two-dimensional -dynamics method to include proton tautomerism in continuous constant pH molecular dynamics (CPHMD) simulations. The two-dimensional -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 pK_a 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 pK_a 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.

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