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Microsecond Timescale Simulations at the Transition State of PmHMGR Predict Remote Allosteric Residues

submitted on 17.10.2019, 20:02 and posted on 21.10.2019, 21:02 by Taylor Quinn, Calvin N. Steussy, Brandon E. Haines, Jinping Lei, Wei Wang, Fu Kit Sheong, Cynthia V. Stauffacher, Xuhui Huang, Per-Ola Norrby, Paul Helquist, Olaf Wiest

Understanding the mechanisms of enzymatic catalysis requires a detailed understanding of the complex interplay of structure and dynamics of large systems that is a challenge for both experimental and computational approaches. QM/MM methods have been extensively used to study these reactions, but the difficulties arising from the hybrid treatment of the system are well documented. More importantly, the computational demands of QM/MM simulations mean that the dynamics of the reaction can only be considered on a timescale of nanoseconds even though the conformational changes needed to react the catalytically active state happen on a much slower timescale. Here we demonstrate an alternative approach that uses transition state force fields (TSFFs) derived by the quantum-guided molecular mechanics (Q2MM) method that provides a consistent treatment of the entire system at the classical molecular mechanics level and allows simulations at the microsecond timescale. Application of this approach the second hydride transfer transition state of HMG-CoA reductase from Pseudomonas mevalonii (PmHMGR) identified three remote residues, R396 E399 and L407, (15-27 Å away from the active site) that have a remote dynamic effect on enzyme activity. The predictions were subsequently validated experimentally via site-directed mutagenesis. These results show that microsecond timescale MD simulations of transition states are possible and can predict rather than just rationalize remote allosteric residues.


Determination of structure, dynamics and energetics of enzyme reactions

National Institute of General Medical Sciences

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Chemistry-Biochemistry-Biology Interface (CBBI) Program at Notre Dame

National Institute of General Medical Sciences

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Email Address of Submitting Author


University of Notre Dame


United States

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Declaration of Conflict of Interest

The authors declare no competing interests.