Quantum And Classical Computational Analysis Of Biological Macromolecules

Computational simulation of the dynamics of biological macromolecules is drawing increasing attention as the processing capacity of computers grows rapidly. By analyzing the dynamics of electromagnetic fields, simulated computations can reproduce microscopic processes of molecular movement, yielding detailed information about the conformational changes of macromolecules, revealing interactions between macromolecules on the atomic level, and predicting quantitatively the mechanical and thermodynamic properties of a microscopic system at rest and in action. During the past few decades, molecular dynamics (MD) simulations have become an important tool and active forefront in the study of biological molecules. Notably, accurate prediction of free energy changes has facilitated understanding of the structure-activity relationship of macromolecules, providing the basis for rational drug design.First discovered by FM Ritossa in the 1960s, heat shock proteins (Hsps) are a class of highly conserved proteins across biological taxa. Recent findings indicate that Hsp90 is a critical component in many oncogenic pathways, playing an important role in carcinogenesis. Consequently, Hsp90 has emerged as a promising target for chemotherapy of tumors. Studies of Hsp90 and its inhibitors is a leading edge in anticancer research.Three pyrazole-based inhibitors of Hsp90, namely, 4BH, 2E1, and 2D9, were analyzed in this study. 2E1 is formed by appending an ethylamido group onto the P1 position of 4BH, while a methylsulphonylbenzyl substituent at position P2 turns 4BH into 2D9. Both substituents include a hydrophobic group, alkyl or phenyl, which may result in enhanced hydrophobic interactions. One purpose of this work is to assess the effects of these two substituents on binding free energy.Five-nanosecond MD simulations were performed on the 4BH-Hsp90, 2E1-Hsp90, and 2D9-Hsp90 complexes. It turned out that the RMSD values of the three complexes were nearly the same. Calculation of binding free energy by the MM-PBSA method demonstrated that van der Waals forces were primarily responsible for driving the binding of the inhibitors to Hsp90. Detailed inhibitor–residue interaction spectra revealed a new and important site of interaction between 2D9 and the Hsp due to the methylsulphonulbenzyl substituent. Structure-affinity analyses showed that substitution at P1 and P2 facilitated binding of 2E1 and 2D9 to Hsp compared with 4BH. These data may assist in designing new potent drugs to combat cancer.Acquired immunodeficiency syndrome (AIDS) is a disease primarily caused by the type 1 Human Immunodeficiency Virus (HIV-1). There are three key enzymes in the replication of the virus, namely, reverse transcriptase (RT), protease (PR), and intergrase (IN). The protease is a homodimer with C2 symmetry, each peptide consisting of 99 amino acids. It functions in the maturation phase of the viral life cycle to produce infectious virion particles. The enzyme has become an important target in anti-AIDS chemotherapy. Since it is an aspartate protease, protonation states of Asp25/Asp25' in the active site is significant in the binding of inhibitors and in determining the effects of amino acid mutations on drug resistance. Development of protease inhibitors remains an active area of theoretical research.The structure-activity relationship of three related inhibitors of the HIV-1 protease, namely, BE4, BE5, and BE6, were analyzed. The inhibitors have C2 symmetry, with distinctively positioned fluorine substitutions on two symmetrical benzyloxy groups. The hydrophobic benzyloxy groups at P1/P1'and the 2-indanol groups at P2/P2'bind hydrophobic pockets in the protease. Two-nanosecond MD simulations were performed on the complexes formed of an inhibitor and the protease. The crystallization water between Ile50/Ile50'and the inhibitor, Wat301, was well maintained in the simulated processes. The stable hydrogen bonds between the Ile50/Ile50'residues, Wat301, and the inhibitor effectively mediated enzyme-inhibitor binding. The values of binding free energy between each of the three inhibitors and the enzyme as predicted with MM-PBSA were in line with empirical findings. Simultaneous energy decomposition with the GBSA method revealed that all residues that contributed significantly to the binding energy formed six interaction groups around Ala28, Ile50, Ile84, Ala28, Ile50', and Ile84'. Moreover, the three inhibitors bound the protease in the same pattern. The pattern of interactions between inhibitors and the protease may provide theoretical guidance for designing new inhibitors.GRL02031(031,(3aS,5R,6aR)-hexahydro-2H-cyclopenta[b]furan-5-yl[(1S,2R)-1- benzyl-2-hydroxy-3-([(4-methoxyphenyl)sulfonyl]{[(2R)-5-oxopyrrolidin-2-yl]methyl}amino)propyl]carbamate) is new drug to inhibit HIV-1 with improved ability to resist viral mutations. MD simulations in combination with calculations of binding free energy were performed to assess the effect of the various protonation states of Asp25/Asp25'on the binding free energy between HIV-1 protease and the 031 inhibitor. In the PR-031 complex, the inhibitor formed separate hydrogen bonds with Asp25 and Asp25'. Protonation states of both aspartate residues affected the enzyme-inhibitor interactions. However, the protonation states were dependent on the structure of the inhibitor and the environment around the complex. No information about protonation states was found in the crystal structures of the PR-031 complex.Five-nanosecond MD simulations were performed to investigate the four most probable protonation states of the PR-031 complex. Binding energy of the complex with various protonation states were calculated using the MM-PBSA method. The GBSA method was used to calculate the interactions between inhibitor 031 and individual amino acid residues of the protease. The results showed that different protonation states significantly affected the dynamic properties, binding free energy, and the mechanisms of PR-031 interactions. Comprehensive analyses indicated that the OD2 protonation state of Asp25 in chain A was the most probable state. Moreover, analysis of hydrogen bonding showed that different protonation states also had some influence on the water bridge. The study provides theoretical guidance for designing high affinity inhibitors and understanding mutation-induced drug resistance.The dissertation primarily consists of three sections. The first section studied the mechanisms of interaction between Hsp90 and its three pyrazole-based inhibitors. The second section studied the structure-activity relationship between the HIV-1 protease and its inhibitors with different fluorine positions on the benzyloxy groups. The third section studied the effect of different protonation states of the aspartate residues in the HIV-1 protease on its interaction with the GRL02031 inhibitor.