This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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.
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