National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia.
J Chem Inf Model. 2012 Oct 22;52(10):2541-9. doi: 10.1021/ci3003254. Epub 2012 Oct 8.
A protocol was developed for the computational determination of the contribution of interfacial amino acid residues to the free energy of protein-protein binding. Thermodynamic integration, based on molecular dynamics simulation in CHARMM, was used to determine the free energy associated with single point mutations to glycine in a protein-protein interface. The hot spot amino acids found in this way were then correlated to structural similarity scores detected by the ProBiS algorithm for local structural alignment. We find that amino acids with high structural similarity scores contribute on average -3.19 kcal/mol to the free energy of protein-protein binding and are thus correlated with hot spot residues, while residues with low similarity scores contribute on average only -0.43 kcal/mol. This suggests that the local structural alignment method provides a good approximation of the contribution of a residue to the free energy of binding and is particularly useful for detection of hot spots in proteins with known structures but undetermined protein-protein complexes.
制定了一种计算方法,用于确定界面氨基酸残基对蛋白质-蛋白质结合自由能的贡献。基于 CHARMM 分子动力学模拟的热力学积分用于确定蛋白质-蛋白质界面中甘氨酸单点突变相关的自由能。通过 ProBiS 算法进行局部结构比对来检测结构相似性得分,从而找到热点氨基酸。我们发现,结构相似性得分高的氨基酸平均对蛋白质-蛋白质结合自由能的贡献为-3.19 kcal/mol,因此与热点残基相关,而相似性得分低的残基平均仅贡献-0.43 kcal/mol。这表明局部结构比对方法很好地近似了残基对结合自由能的贡献,并且特别适用于检测具有已知结构但未确定蛋白质-蛋白质复合物的蛋白质中的热点。