Design and application ofrobust and efficient QM/MM free energy simulation methods for biomolecular systems

University Of South Florida, Tampa FL

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Abstract

Project Summary/Abstract To accurately compute free energies and reaction profiles of complex biomolecular systems and reactions there are two key prerequisites: the accurate description of inter- and intramolecular interactions, and adequate sampling of all relevant conformational degrees of freedom. Include the possibility that conformational dynamics may be coupled to complex electronic processes or chemical reactions, where quantum mechanical (QM) methods are needed, and this task becomes extremely daunting. Currently, whenever accurate computations of biomolecular systems are essential, the tool of choice is hybrid quantum mechanical/molecular mechanical (QM/MM) calculations, however, the application of these techniques to free energy simulations (FES) is still far from routine. Herein, we aim to develop a set of robust, efficient, and accurate new techniques that will make the application of QM/MM FES practical. These methods will be subsequently applied to study two classes of biomolecular applications that present extreme challenges to current techniques: (1) studying processes where conformational changes may be coupled to enzyme catalysis, as in 1-Deoxy- D-xylulose 5-phosphate synthase (DXPS), a key enzyme in the metabolic pathway of pathogenic bacteria, absent in humans and therefore a potential drug target; and (2) investigating the binding step in covalent inhibition of serine β- lactamases, one strategy to overcome antimicrobial resistance.