Collective dynamics and conformational sampling of triosephosphate isomerase

Abstract

Molecular dynamics simulations (30-60 ns runs) are performed on free/apo triosephosphate isomerase (TIM) to determine any correlation between collective motions and loop 6 dynamics. Native TIM is active only as a homo-dimer even though cooperativity has not been observed between the two identical subunits. Both dimeric and monomeric (isolated from dimer) forms of TIM are simulated in explicit water at 300 K and 1 bar to inspect any differences between the structures in terms of fluctuation dynamics and functionally important loop 6 dynamics/closure. Significant crosscorrelations between residue fluctuations are observed in the dimer, which result from the global counter-rotations of the two identical subunits in the essential modes of the dimer. Specifically, the first essential mode contributing to 34% of overall motion of the dimer is strongly coupled to the loop 6’s closure over the active site. In contrast, such significant correlations cannot be observed in the monomeric structure, which maintains relatively localized motions of the loops in the essential modes. Thus, the onset of collective motions at ns timescale due to dimerization has functional implications as to the coordination of loop 6 closure. Additionally, a new technique for conformational sampling of proteins is proposed in this thesis, which combines elastic network models and energy minimization procedure. Different conformations generated along the slow harmonic normal modes are reverse-mapped by energy minimization using the generalized Born, implicit solvation model. The applicability and efficiency of this approach is demonstrated on dimeric TIM using the 60 ns MD trajectory.