Center for Molecular Modeling - BOF T. Verstraelen BOFSTA2017004901

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

The local response of global descriptors

wim — Wed, 15 Feb 2017 11:01:59 +0000

F. Heidar-Zadeh, S. Fias, E. Vohringer-Martinez, T. Verstraelen, P.W. Ayers

Theoretical Chemistry Accounts

136 (1), 19

2017

Abstract

We consider the problem of defining an appropriate local descriptor corresponding to an arbitrary global descriptor. Although it does not seem easy to rigorously and uniquely define local analogues of derived global descriptors (e.g., the electrophilicity) or the fundamental global descriptors associated with the canonical ensemble (e.g., the hardness), the local response of these global descriptors can be defined unambiguously. We look at the local response of the global electrophilicity and compare it to the conventional, ad hoc, definition of the local electrophilicity. The local response of global nucleofugality and electrofugality is also discussed.

DOI

http://dx.doi.org/10.1007/s00214-016-2036-0

Private attachment

art%3A10.1007%2Fs00214-016-2036-0.pdf

Ruben Goeminne

wim — Mon, 04 Sep 2017 06:43:01 +0000

ACS 253rd National Meeting & Exposition

wim — Wed, 12 Apr 2017 10:51:08 +0000

San Francisco, USA

Sunday, 2 April, 2017 to Thursday, 6 April, 2017

Participant(s)

K. De Wispelaere, T. Verstraelen

Project ref.

FWO K. De Wispelaere FWO3E02016000901, BOF T. Verstraelen BOFSTA2017004901

Conference reference

ACS 253rd National Meeting & Exposition

Starters grant

wim — Wed, 29 Mar 2017 08:08:11 +0000

Project promotor

T. Verstraelen

Financierende instantie

BOF

Project data

01/01/2017 to 31/12/2021

Bedrag

€76 600,00

Project titel

STA066-17

Project ref.

BOF T. Verstraelen BOFSTA2017004901

Andreas Luttens

wim — Tue, 10 Jan 2017 09:38:54 +0000