MCCE2: improving protein pKa calculations with extensive side chain rotamer sampling.
MCCE2: improving protein pKa calculations with extensive side chain rotamer sampling.
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DOI：
10.1002/jcc.21222
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发表时间：
2009-11-15
影响因子：
3
通讯作者：
Gunner, M. R.
中科院分区：
文献类型：
--
作者：
Song, Yifan;Mao, Junjun;Gunner, M. R.
多构象连续静电学（MCCE）在蛋白质残基和配体pKas的Monte Carlo计算中探索了不同的构象自由度。整个滴定过程中侧链构象的显式变化产生了位置依赖性，异质介电响应，从而提供了更准确的耦合电离和位置变化的图像。描述了选择一组输入重原子和质子位置的MCCE 2方法。不同的电子等排构象，重原子旋转异构体和质子的位置，具有不同程度的优化计算的pKa进行了测试，对33种蛋白质的305个实验pKa的策划组。快速计算，围绕Asn和Gln末端旋转，对His互变异构体和扭转最小羟基进行采样，得到RMSD为1.34，84%的误差<1.5 pH单位。添加重原子旋转异构体和侧链优化的完整计算产生0.90的RMSD，90%的误差<1.5 pH单位。在膜蛋白细菌视紫红质中也发现了良好的结果。额外的侧链位置的列入扭曲的介电边界，也通过创建更多的中性比电离构象偏置计算的pKa。介绍了修正这些误差的方法。计算结果与36种可溶性蛋白质中的多个X射线和NMR衍生结构进行了比较。用X射线结构的计算给出了显著更好的pKa。默认蛋白质介电常数为4的结果与使用值8的结果一样好。
Multiconformation continuum electrostatics (MCCE) explores different conformational degrees of freedom in Monte Carlo calculations of protein residue and ligand pKas. 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 pKas 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 pKas 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 pKas in the membrane protein bacteriorhodopsin. The inclusion of extra side chain positions distorts the dielectric boundary and also biases the calculated pKas 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 pKas. Results with the default protein dielectric constant of 4 are as good as those using a value of 8.
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影响因子：
2.9
作者：
Antosiewicz, J;McCammon, JA;Gilson, MK
通讯作者：
Gilson, MK
影响因子：
2.9
作者：
BRAIMAN, MS;MOGI, T;ROTHSCHILD, KJ
通讯作者：
ROTHSCHILD, KJ
影响因子：
2.9
作者：
Bollinger, JG;Diraviyam, K;Gelb, MH
通讯作者：
Gelb, MH
影响因子：
5.6
作者：
ANTOSIEWICZ, J;MCCAMMON, JA;GILSON, MK
通讯作者：
GILSON, MK
影响因子：
3
作者：
BROOKS, BR;BRUCCOLERI, RE;KARPLUS, M
通讯作者：
KARPLUS, M