Prediction and rationalization of protein pKa values using QM and QM/MM methods

被引:121
作者
Jensen, JH [1 ]
Li, H
Robertson, AD
Molina, PA
机构
[1] Univ Iowa, Ctr Biocatalysis & Bioproc, Dept Chem, Iowa City, IA 52242 USA
[2] Univ Iowa, Dept Biochem, Iowa City, IA 52242 USA
关键词
D O I
10.1021/jp051922x
中图分类号
O64 [物理化学(理论化学)、化学物理学];
学科分类号
070304 ; 081704 ;
摘要
We describe the development and application of a computational method for the prediction and rationalization of pK(a) values of ionizable residues in proteins, based on ab initio quantum mechanics (QM) and the effective fragment potential (EFPs) method (a hybrid QM/MM method). The theoretical developments include (1) a covalent boundary method based on frozen localized orbitals, (2) divide-and-conquer methods for the ab initio computation of protein EFPs consisting of multipoles up to octupoles and dipole polarizability tensors, (3) a method for computing vibrational free energies for a localized molecular region, and (4) solutions of the polarized continuum model of bulk solvation equations for protein-sized systems. The QM-based pK(a) prediction method is one of the most accurate methods currently available and can be used in cases where other pK(a) prediction methods fail. Preliminary analysis of the computed results indicate that many pK(a) values (1) are primarily determined by hydrogen bonds rather than long-range charge-charge interactions and (2) are relatively insensitive to large-scale dynamical fluctuations of the protein structure.
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收藏
页码:6634 / 6643
页数:10
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