CONTINUUM ELECTROSTATISTICS THEORY

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。在研究蛋白质与配体的相互作用时，人们往往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，直接的相互作用并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会发生改变。这种介电环境的变化可以引入溶解惩罚，并改变蛋白质和配体中溶剂介导的分子内相互作用。例如，考虑一个靠近蛋白质-配体界面的配体原子。它在粘合前相对暴露于溶剂，但粘合后暴露较少。因此，在绑定时产生解绑定惩罚。此外，由于溶剂分子在结合袋中的位移，该原子的电荷在结合后较少被溶剂屏蔽，因此它与其他原子的静电相互作用的强度，不仅与蛋白质的相互作用，而且与配体本身的相互作用，由于有效介电常数的降低而增加。因此，在研究蛋白质与配体结合时，除了蛋白质与配体之间的直接和溶剂介导的相互作用外，重要的是要检查每个原子的溶剂化能的变化，以及溶剂介导的配体内部和蛋白质内部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. 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.