Predicting the Acid/Base Behavior of Proteins: A Constant-pH Monte Carlo Approach with Generalized Born Solvent

被引:27
作者
Aleksandrov, Alexey [2 ]
Polydorides, Savvas [1 ]
Archontis, Georgios [1 ]
Simonson, Thomas [2 ]
机构
[1] Univ Cyprus, Dept Phys, CY-1678 Nicosia, Cyprus
[2] Ecole Polytech, CNRS, Biochim Lab, Dept Biol,UMR7654, F-91128 Palaiseau, France
关键词
MOLECULAR-DYNAMICS SIMULATIONS; ELECTROSTATIC FREE-ENERGY; ENZYME ACTIVE-SITE; DIELECTRIC-PROPERTIES; POISSON-BOLTZMANN; TITRATION CURVES; PK(A) VALUES; TRYPSIN-INHIBITOR; CONTINUUM MODELS; IONIZABLE GROUPS;
D O I
10.1021/jp104406x
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
The acid/base properties of proteins are essential in biochemistry, and proton binding is a valuable reporter on electrostatic interactions. We propose a constant-pH Monte Carlo strategy to compute protonation free energies and pK(a)'s. The solvent is described implicitly, through a generalized Born model. The electronic polarizability and backbone motions of the protein are included through the protein dielectric constant. Side chain motions are described explicitly, by the Monte Carlo scheme. An efficient computational algorithm is described, which allows us to treat the fluctuating shape of the protein/solvent boundary in a way that is numerically exact (within the GB framework); this contrasts with several previous constant-pH approaches. For a test set of six proteins and 78 titratable groups, the model performs well, with an rms error of 1.2 pH units. While this is slightly greater than a simple Null model (rms error of 1.1) and a fully empirical model (rms error of 0.9), it is obtained using physically meaningful model parameters, including a low protein dielectric of four. Importantly, similar performance is obtained for side chains with large and small pK(a) shifts (relative to a standard model compound). The titration curve slopes and the conformations sampled are reasonable. Several directions to improve the method further are discussed.
引用
收藏
页码:10634 / 10648
页数:15
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