Teng Shaolei, Madej Thomas, Panchenko Anna, Alexov Emil
Computational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, South Carolina, USA.
Biophys J. 2009 Mar 18;96(6):2178-88. doi: 10.1016/j.bpj.2008.12.3904.
A large set of three-dimensional structures of 264 protein-protein complexes with known nonsynonymous single nucleotide polymorphisms (nsSNPs) at the interface was built using homology-based methods. The nsSNPs were mapped on the proteins' structures and their effect on the binding energy was investigated with CHARMM force field and continuum electrostatic calculations. Two sets of nsSNPs were studied: disease annotated Online Mendelian Inheritance in Man (OMIM) and nonannotated (non-OMIM). It was demonstrated that OMIM nsSNPs tend to destabilize the electrostatic component of the binding energy, in contrast with the effect of non-OMIM nsSNPs. In addition, it was shown that the change of the binding energy upon amino acid substitutions is not related to the conservation of the net charge, hydrophobicity, or hydrogen bond network at the interface. The results indicate that, generally, the effect of nsSNPs on protein-protein interactions cannot be predicted from amino acids' physico-chemical properties alone, since in many cases a substitution of a particular residue with another amino acid having completely different polarity or hydrophobicity had little effect on the binding energy. Analysis of sequence conservation showed that nsSNP at highly conserved positions resulted in a large variance of the binding energy changes. In contrast, amino acid substitutions corresponding to nsSNPs at nonconserved positions, on average, were not found to have a large effect on binding affinity. pKa calculations were performed and showed that amino acid substitutions could change the wild-type proton uptake/release and thus resulting in different pH-dependence of the binding energy.
利用基于同源性的方法构建了264个蛋白质-蛋白质复合物的大量三维结构，这些复合物在界面处具有已知的非同义单核苷酸多态性（nsSNPs）。将nsSNPs映射到蛋白质结构上，并使用CHARMM力场和连续静电计算研究它们对结合能的影响。研究了两组nsSNPs：疾病注释的《人类在线孟德尔遗传》（OMIM）和未注释的（非OMIM）。结果表明，与非OMIM nsSNPs的作用相反，OMIM nsSNPs倾向于使结合能的静电成分不稳定。此外，研究表明，氨基酸替换时结合能的变化与界面处净电荷、疏水性或氢键网络的保守性无关。结果表明，一般来说，仅从氨基酸的物理化学性质无法预测nsSNPs对蛋白质-蛋白质相互作用的影响，因为在许多情况下，用具有完全不同极性或疏水性的另一种氨基酸替换特定残基对结合能影响很小。序列保守性分析表明，高度保守位置的nsSNP导致结合能变化的差异很大。相比之下，未保守位置的nsSNP对应的氨基酸替换平均而言对结合亲和力没有很大影响。进行了pKa计算，结果表明氨基酸替换可能会改变野生型质子的摄取/释放，从而导致结合能具有不同的pH依赖性。
