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首页> 外文期刊>Physical chemistry chemical physics: PCCP >Insights into affinity and specificity in the complexes of α-lytic protease and its inhibitor proteins: binding free energy from molecular dynamics simulation
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Insights into affinity and specificity in the complexes of α-lytic protease and its inhibitor proteins: binding free energy from molecular dynamics simulation

机译：深入了解α-分解蛋白酶及其抑制剂蛋白复合物中的亲和力和特异性：结合分子动力学模拟获得的自由能

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摘要

We report the binding free energy calculation and its decomposition for the complexes of a-lytic protease and its protein inhibitors using molecular dynamics simulation. Standard mechanism serine protease inhibitors eglin C and OMTKY3 are known to have strong binding affinity for many serine proteases. Their binding loops have significant similarities, including a common P1 Leu as the main anchor in the binding interface. However, recent experiments demonstrate that the two inhibitors have vastly different affinity towards a-lytic protease (ALP), a bacterial serine protease. OMTKY3 inhibits the enzyme much more weakly (by ~ 106 times) than eglin C. Moreover, a variant of OMTKY3 with five mutations, OMTKY3M, has been shown to inhibit 104 times more strongly than the wild-type inhibitor. The underlying mechanisms for the ? unusually large difference in binding affinities and the effect of mutation are not well understood. Here we use molecular dynamics simulation with molecular mechanics-Poisson Boltzmann/ surface area method (MM-PB/SA) to investigate quantitatively the binding specificity. The calculated absolute binding free energies correctly differentiate the thermodynamic stabilities of these protein complexes, but the magnitudes of the binding affinities are systematically overestimated. Analysis of the binding free energy components provides insights into the molecular mechanism of binding specificity. The large ΔΔG_(bind) between eglin C and wild type OMTKY3 towards ALP is mainly attributable to the stronger nonpolar interactions in the ALP-eglin C complex, arising from a higher degree of structural complementarity. Here the electrostatic interaction contributes to a lesser extent. The enhanced inhibition in the penta-mutant OMTKY3M over its wild type is entirely due to an overall improvement in the solvent-mediated electrostatic interactions in the ALP-OMTKY3M complex. The results suggest that for these protein-complexes and similar enzyme-inhibitor systems (1) the binding is driven by nonpolar interactions, opposed by overall electrostatic and solute entropy contributions; (2) binding specificity can be tuned by improving the complementarity in electrostatics between two associating proteins. Binding free energy decomposition into contributions from individual protein residues provides additional detailed information on the structural determinants and subtle conformational changes responsible for the binding specificity.
机译：我们报告结合自由能的计算和分解使用分子动力学模拟的a-分解蛋白酶及其蛋白抑制剂的复合物。已知标准机制的丝氨酸蛋白酶抑制剂例如C蛋白C和OMTKY3对许多丝氨酸蛋白酶具有很强的结合亲和力。它们的绑定环具有显着的相似性，包括一个常见的P1 Leu作为绑定界面中的主要锚点。但是，最近的实验表明，这两种抑制剂对细菌丝氨酸蛋白酶a-分解蛋白酶（ALP）的亲和力差别很大。 OMTKY3对酶的抑制作用比eglin C弱得多（约106倍）。此外，具有五个突变的OMTKY3变体OMTKY3M的抑制作用比野生型抑制剂强104倍。潜在的机制？尚不十分清楚结合亲和力的异常差异和突变的影响。在这里，我们使用分子力学-泊松玻尔兹曼/表面积法（MM-PB / SA）进行分子动力学模拟来定量研究结合特异性。计算的绝对结合自由能正确地区分了这些蛋白质复合物的热力学稳定性，但是结合亲和力的大小被系统地高估了。结合自由能成分的分析提供了对结合特异性的分子机制的见解。 eglin C和野生型OMTKY3之间对ALP的较大ΔΔG_（bind）主要归因于ALP-eglin C复合物中更强的非极性相互作用，这是由于较高的结构互补性引起的。在此，静电相互作用的贡献程度较小。五突变体OMTKY3M与野生型相比，抑制作用的增强完全归因于ALP-OMTKY3M复合物中溶剂介导的静电相互作用的全面改善。结果表明，对于这些蛋白质复合物和类似的酶抑制剂系统（1），结合是由非极性相互作用驱动的，而与整体静电和溶质熵的贡献相反; （2）结合特异性可以通过改善两个关联蛋白之间的静电互补性来调节。结合自由能分解成单个蛋白质残基的贡献，提供了有关结构决定簇和负责结合特异性的微妙构象变化的更多详细信息。

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