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.Keywords:Molecular dynamics, classical mechanics, quantum mechanics, coupled quantum and classical potentials, free energy perturbation, potential of mean force, divide and conquer, NMRAbstract:In this proposal we are requesting supercomputer time for the next three years to fund Quantum Biology research. As a result of our analysis we are requesting 165K node hours per year on Rachel and 420K node hours per year on Lemieux. The projects to be pursued include: Project 1-Theoretical Studies of the Urease Catalytic Mechanism The catalytic mechanism of urease is still not well understood. Ongoing research has lead us to postulate that an elimination mechanism can compete with the generally preferred hydrolytic one.1,2 In order to complete this project we will carry out molecular dynamics (MD) simulations to elucidate the protonation pattern within the urease active site.3 We will also carry out ab initio and density functional theory (DFT) calculations to study cluster models of the active site in order to map out the elimination reaction pathway in detail and compare it to previous quantum mechanical (QM) work on the hydrolytic pathway. Project 2- A Panoramic View of the Catalytic Mechanism of Farnesyltransferase Farnesyltransferase (FTase) is a zinc enzyme that has been extensively studied by X-ray crystallography, site-directed mutagenesis, and kinetic experiments, trying to capture the essentials of its catalytic power. A series of crystal structures that provide snapshots of each stage of the enzyme action have been made available, which presents an ideal opportunity for exercising and refining theoretical tools. Here we propose a combined MD, and QM investigation of every step of the enzymatic reaction, up to the rate-limiting product release step. Our primary aim is to generate a panoramic view of the FTase reaction and provide guidance for the design of FTase inhibitors that could aid in the treatment of cancer. Project 3-QM Studies of the Chorismate Mutase Catalytic Mechanism This project will compare results obtained from full QM calculations with those from quantum mechanical/molecular mechanical (QM/MM) models with varying sizes of the QM region. The chorismate mutase (CM) system (6,000 atoms)4 will be modeled with semiempirical QM, and the reaction pathway of the enzyme catalyzed Claisen rearrangement will be calculated. The results will be compared with those derived from semiempirical QM/MM approaches. The goal of this project is to begin to understand the limitations of the QM/MM approach relative to the full QM one as well as providing insight into CM catalysis. This will serve as a useful benchmark in order to better understand the accuracy of QM/MM approaches and will allow for the better design of QM/MM models for bigger systems like urease and FTase, for example, Project 4 Scoring of Structural Models by NMR We propose to explore new approaches to calculate Nuclear Magnetic Resonance (NMR) chemical shifts with QM and to apply these approaches to study biological systems. Recently, we have developed a fast approach to accurately calculate NMR chemical shifts using the divide-and-conquer method at the semiempirical MNDO level. This approach enables us to study NMR properties for systems of several thousands of atoms using current supercomputer facilities and, hence, to tackle fundamental biological problems such as predicting the structure of protein-ligand complexes and the prediction of the 3-D structure of proteins.
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