| This dissertation involves the development of novel computational method for efficient linear scaling quantum mechanical ab initio computation of protein-ligand interaction energy, the study of inhibitor bindings to important protein target for AIDS treatment, and the design of more effective inhibitors with stronger binding energy using a comprehensive suite of computational methods.; The new theoretical method, termed molecular fractionation with conjugate caps (MFCC), aims to provide accurate prediction of structure and interaction energy of protein-ligand complex based on high efficiency first principle quantum mechanical computation. This new method provides a unique opportunity for application in structure-based drug design and general protein-ligand interactions by providing more accurate quantum mechanical protein energies beyond the force field approach. The proposed MFCC approach is linear scaling, easy to apply, and computationally efficient for large-scale applications in protein and other biological systems.; Specific application to studying inhibitor binding to HIV-1 protease was carried out to characterize, understand, and design new inhibitors with stronger binding energy and better resistance to HIV virus mutations. Through combination of various computational approaches including molecular dynamics (MD) simulation as well as various empirical methods, the binding free energies of designed HIV-1 protease inhibitors were estimated. |
