MODELING OF CONTRIBUTION OF PARTIAL CHARGES TO PROTEIN-LIGAND

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 使用泊松连续体静电理论对部分电荷对蛋白质-配体相互作用的贡献进行建模 在研究蛋白质-配体相互作用时，人们通常侧重于分析蛋白质与配体原子/官能团/残基之间的直接相互作用。然而，直接相互作用不是决定结合亲和力值的唯一因素。当配体与受体结合时，配体和受体的介电环境都发生了变化。介电环境中的这种变化可以引入去溶剂化惩罚并改变蛋白质和配体中溶剂介导的分子内相互作用。例如，考虑蛋白质-配体界面附近的配体原子。它在粘合之前相对暴露于溶剂，但在粘合之后暴露较少。因此，在结合时产生去溶剂化惩罚。此外，由于该原子的电荷在结合后由于结合袋中溶剂分子的位移而较少被溶剂屏蔽，因此其与其他原子（不仅是与蛋白质的原子，而且是与配体本身内的原子）的静电相互作用的强度由于有效介电常数的减小而增加。因此，在研究蛋白质-配体结合时，重要的是检查每个原子的溶剂化能的变化，以及除了蛋白质和配体之间的直接和溶剂介导的相互作用之外，配体和蛋白质内的溶剂介导的分子内相互作用的变化。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Full Title: Modeling of contribution of partial charges to protein-ligand interactions using Poisson continuum electrostatics theory In studying protein-ligand interactions, one often focuses on analyzing the direct interactions between protein and ligand atoms/functional groups/residues. However, direct interactions are not the only factors that determine the value of a binding affinity. When a ligand binds to a receptor, the dielectric environments of both the ligand and the receptor are changed. This change in dielectric environments can introduce a desolvation penalty and alter the solvent-mediated intramolecular interactions in the protein and the ligand. For example, consider an atom of the ligand near the protein-ligand interface. It is relatively exposed to solvent before but is less exposed after binding. Therefore, a desolvation penalty results upon binding. Also, because the charge of this atom is less screened by the solvent after binding due to the displacement of solvent molecules in the binding pocket, the strength of its electrostatic interactions with other atoms, not only those with the proteins but also those within the ligand itself, is increased because of the diminished effective dielectric constant. Thus, in studying protein-ligand binding, it is important to examine the change in the solvation energy of each atom, and the change in the solvent-mediated intramolecular interactions within the ligand and within the protein in addition to the direct and solvent-mediated interactions between the protein and the ligand.