Proteins have evolved to perform their targeted biochemical function precisely and efficiently. Growing evidence from experiments and computational approaches suggests an intimate synergy between an enzyme's structure, intrinsic dynamics and biochemical function. In this thesis, we investigate the role of intrinsic dynamics in enzyme catalysis by developing novel theoretical and computational techniques and using extensive atomistic level molecular dynamics simulations.

First, we show that there is significant similarity in collective conformational fluctuations during an enzyme's reaction-cycle. In particular, for the enzyme cyclophilin A, a peptidyl-prolyl isomerase, we show that there is substantial overlap (65%) in the dynamics before, during and after the catalytic step. Second, we show that dynamics associated with the catalytic step is evolutionarily conserved in multiple enzymes catalyzing the same biochemical reaction, even when they do not share a common fold. Finally, we show that there is a remarkable similarity in the fluctuations coupled to the catalytic step for several members of a super-family of enzymes sharing a common mechanistic substep in the reaction mechanism. The Rossmann fold family of enzymes investigated reveals the presence of three specific regions shared by all family members that exhibit collective fluctuations coupled to the catalytic step. These regions show the presence of a network formed by hydrogen bonds and hydrophobic interactions extending from the flexible surface regions all the way to the active site.

Our results indicate that intrinsic dynamics coupled to the catalytic step of enzymes may have imposed selective pressure over the course of evolution to promote biochemical function. These observations may have far-reaching implications in understanding how enzymes have evolved and may potentially serve as guiding principles for designing novel enzymes in industrial and therapeutic applications.

225 pages

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