MCCE2: Improving protein pKa calculations with extensive side chain rotamer sampling

✍ Scribed by Yifan Song; Junjun Mao; M. R. Gunner

• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: English
• Weight: 316 KB
• Volume: 30
• Category: Article
• ISSN: 0192-8651
• DOI: 10.1002/jcc.21222

✦ Synopsis

Abstract

Multiconformation continuum electrostatics (MCCE) explores different conformational degrees of freedom in Monte Carlo calculations of protein residue and ligand p__K__~a~s. Explicit changes in side chain conformations throughout a titration create a position dependent, heterogeneous dielectric response giving a more accurate picture of coupled ionization and position changes. The MCCE2 methods for choosing a group of input heavy atom and proton positions are described. The p__K__~a~s calculated with different isosteric conformers, heavy atom rotamers and proton positions, with different degrees of optimization are tested against a curated group of 305 experimental p__K__~a~s in 33 proteins. QUICK calculations, with rotation around Asn and Gln termini, sampling His tautomers and torsion minimum hydroxyls yield an RMSD of 1.34 with 84% of the errors being <1.5 pH units. FULL calculations adding heavy atom rotamers and side chain optimization yield an RMSD of 0.90 with 90% of the errors <1.5 pH unit. Good results are also found for p__K__~a~s in the membrane protein bacteriorhodopsin. The inclusion of extra side chain positions distorts the dielectric boundary and also biases the calculated p__K__~a~s by creating more neutral than ionized conformers. Methods for correcting these errors are introduced. Calculations are compared with multiple X‐ray and NMR derived structures in 36 soluble proteins. Calculations with X‐ray structures give significantly better p__K__~a~s. Results with the default protein dielectric constant of 4 are as good as those using a value of 8. The MCCE2 program can be downloaded from http://www.sci.ccny.cuny.edu/∼mcce. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009