Dissertations, Theses, and Capstone Projects
Date of Degree
2-2025
Document Type
Dissertation
Degree Name
Ph.D.
Program
Biochemistry
Advisor
Emilio Gallicchio
Committee Members
Themis Lazaridis
Tom Kurtzman
Angelo Bongiorno
Ron Levy
Subject Categories
Biological and Chemical Physics | Computational Chemistry
Keywords
Free Energy Perturbation, Binding Free Energy Estimation, Drug Discovery, Molecular Dynamics Simulation, Structure-Based Drug Design
Abstract
Molecular recognition is fundamental to all biological and biochemical processes. Understanding the interactions between molecules is the foundation for drug discovery and development, for understanding biological processes, and for the design of biosensors and nanomaterials. There is tremendous interest in the development of computer models to predict molecular association equilibria. In structure-based drug discovery enterprises, predicting the strength and selectivity of a small molecule to a biological target can advance target identification, aid ligand design, and accelerate high-throughput screening of drug compounds. This work focuses on free energy models, a class of computational methodologies grounded on the fundamental physical and chemical principles that govern molecular recognition. Within this domain exists a rich tool kit that the academic and industrial community continues to contribute to, through the development and refinement of force fields, potential energy functions, solvation models, and sampling techniques. We have developed a new methodology, known as the alchemical transfer method, to incorporate into this tool kit. The method was developed for the purpose of streamlining binding free energy calculations and accommodating the latest innovations in the field. The alchemical transfer method is the unifying force within this work.
In the first chapter, an introduction to modern physics-based models of binding free energy is presented. I include a simplified, statistical mechanical theory of non-covalent molecular binding that forms the foundation of physics-based free energy models. Chapter 1 also refines the focus on to alchemical free energy models of binding, which is a staple of drug discovery and design practices. The alchemical transfer method is formally introduced and reviewed in Chapter 2. Several foundational studies are examined to highlight the method’s significance and utility, and to uncover its limitations and domain of applicability. In Chapter 3, an analytical description of the alchemical transfer method for molecular binding using the potential distribution theorem is established. The third chapter provides a solid theoretical basis for direct alchemical transfer and confirms the conceptual and numerical equivalence between the transfer method and the step-wise, double-decoupling method. In Chapter 4, the hydrophobic phenomena is investigated for small polar molecules and nonpolar hydrocarbons. We offer physical insights on the form of the probability densities of solute-solvent interactions for hydrophobic hydration. In the final chapter, the latest developments of the alchemical transfer method are presented. The novel protocols are applied to conduct multi-target selectivity analysis of small molecules to hosts and proteins. The theories and methodologies presented in this work are for the intent of advancing computational models of molecular binding.
Recommended Citation
Azimi, Solmaz, "Novel Alchemical Methodologies for Modeling Molecular Binding" (2025). CUNY Academic Works.
https://academicworks.cuny.edu/gc_etds/6159
