Center for Molecular Modeling - S.K. Burger

Exploring the substrate selectivity of human sEH and M. tuberculosis EHB using QM/MM

wim — Tue, 19 Sep 2017 14:04:31 +0000

S. Rabi, A.H.G. Patel, S.K. Burger, T. Verstraelen, P.W. Ayers

Structural Chemistry

28 (5), 1501-1511

2017

Abstract

The mechanisms of human soluble epoxide hydrolase (sEH) and the corresponding epoxide hydrolase enzyme from Mycobacterium tuberculosis (EHB) are studied computationally, using the quantum mechanics/molecular mechanics (QM/MM) method. To do this, we modeled the alkylation and the hydrolysis steps of three substrates: trans-1,3-diphenylpropene oxide, trans-stilbene oxide and cis-stilbene oxide. Studying the regioselectivity for trans-1,3-diphenylpropene oxide, we determined that both enzymes prefer ring opening via attack on the benzylic carbon. In agreement with experimental studies, our computations show that the rate-limiting step is hydrolysis of the ester intermediate, with reaction barriers of approximately 13 to 18 kcal/mol. Using the barrier energies of this rate-limiting step, the three epoxides were ranked in order of reactivity. Though the reactivity order was correctly predicted for sEH, the predicted order for EHB did not correspond to experimental observations. Next, the electrostatic contributions of individual residues on the barrier height of the rate-limiting step were also studied. This revealed several residues important for catalysis. The secondary tritium kinetic isotope effect for the alkylation step was determined using a cluster model for the active site of sEH. The calculated value was 1.27, suggesting a late transition state for the rate-limiting step. Finally, we analyzed the reactivity trends using reactivity indicators from conceptual density functional theory, allowing us to identify ease of electron transfer as the primary driving force for the reaction.

DOI

https://doi.org/10.1007/s11224-017-0982-3

Private attachment

s11224-017-0982-3.pdf

Automated Parametrization of AMBER Force Field Terms from Vibrational Analysis with a Focus on Functionalizing Dinuclear Zinc(II) Scaffolds

wim — Wed, 28 Mar 2012 09:27:46 +0000

S.K. Burger, M. Lacasse, T. Verstraelen, J.A. Drewry, P.T. Gunning, P.W. Ayers

Journal of Chemical Theory and Computation (JCTC)

8 (2), 554-562

2012

Abstract

A procedure for determining force constants that is independent of the internal redundant coordinate choice is presented. The procedure is based on solving each bond and angle term separately, using the Wilson B matrix. The method only requires a single ab initio frequency calculation at the minimum energy structure and is made available in the software "parafreq". The methodology is validated with a set of small molecules, by showing it can reproduce ab initio frequencies better than other methods such as taking the diagonal terms of the Hessian in internal coordinates or by using standard AMBER force fields. Finally, the utility of the method is demonstrated by parametrizing the dizinc scaffold of bis-dipicolylamine (BDPA) bound to phosphotyrosine, which is then functionalized into promising antitumor drug proteomimetics.

DOI

http://dx.doi.org/10.1021/ct2007742

Private attachment

12 j. chem. theory comput 8(2)554 Burger.pdf

Robust methods for predicting the transition states of chemical reactions: New approaches that focus on key coordinates

toon — Thu, 14 Nov 2013 13:53:01 +0000

P.W. Ayers, S. Rabi, T. Verstraelen, S.K. Burger

ISBN/ISSN:

Talk

Conference / event / venue

ACS Spring Meeting

New Orleans, US

Monday, 8 April, 2013 to Friday, 12 April, 2013

Abstract (private)

2013_ACS_Ayers.pdf