Dissertations, Theses, and Capstone Projects
Date of Degree
2-2025
Document Type
Dissertation
Degree Name
Ph.D.
Program
Chemistry
Advisor
Emilio Gallicchio
Advisor
Thomas Kurtzman
Committee Members
Nicolas Giovambattista
Subject Categories
Computational Chemistry | Medicinal-Pharmaceutical Chemistry | Physical Chemistry
Keywords
Statistical Mechanics, Molecular Binding, Binding Free Energy, Water Structure and Solvation Thermodynamics, Confined Hydration, ADMET
Abstract
An important factor in guiding the development of drug discovery efforts is the comprehensive assessment of a ligand or drug’s ability to bind its receptor. The metric used to measure this interaction strength is by calculating the binding free energy (BFE). To achieve this accurately, we combine two concepts: (1) Grid Inhomogeneous Solvation Theory (GIST) returns the local water thermodynamic and structural contributions to free energy; and the (2) Alchemical Transfer Method (ATM) obtains the absolute (ABFE) and relative binding free energy (RBFE) estimates between ligand pairs. In this work, we employ Alchemical Water-Transfer to tether bridging water(s) during the alchemical transformation. Together with GIST, the insight obtained from understanding water’s behavior in confined, or more notably, occluded spaces, gives a more complete picture of water’s contribution to binding. Especially relevant for the case of occluded sites, Alchemical Water-Transfer uniquely handles ligand pairs that bind different numbers of bridging waters, in which careful accounting and placement of these mediating waters yield a more accurate evaluation of the RBFE.
Recommended Citation
Wu, Joe Z., "The Role of Confined Hydration and Water Reorganization in Molecular Binding" (2025). CUNY Academic Works.
https://academicworks.cuny.edu/gc_etds/6189
Included in
Computational Chemistry Commons, Medicinal-Pharmaceutical Chemistry Commons, Physical Chemistry Commons
