Using the Relative Energy Gradient Method with Interacting Quantum Atoms to Determine the Reaction Mechanism and Catalytic Effects in the Peptide Hydrolysis in HIV-1 Protease.

Joseph C R Thacker,Paul L A Popelier,Mark A Vincent

doi:10.1002/chem.201802035

Joseph C R Thacker, Paul L A Popelier + Show 1 more

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https://doi.org/10.1002/chem.201802035

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Abstract

The reaction mechanism in an active site is of the utmost importance when trying to understand the role that an enzyme plays in biological processes. In a recently published paper [Theor. Chem. Acc. 2017, 136, 86], we formalised the Relative Energy Gradient (REG) method for automating an Interacting Quantum Atoms (IQA) analysis. Here, the REG method is utilised to determine the mechanism of peptide hydrolysis in the aspartic active site of the enzyme HIV‐1 Protease. Using the REG method along with the IQA approach we determine the mechanism of peptide hydrolysis without employing any arbitrary parameters and with remarkable ease (albeit at large computational cost: the system contains 133 atoms, which means that there are 17 689 individual IQA terms to be calculated). When REG and IQA work together it is possible to determine a reaction mechanism at atomistic resolution from data directly derived from quantum calculations, without arbitrary parameters. Moreover, the mechanism determined by this novel method gives concrete insight into how the active site residues catalyse peptide hydrolysis.

Highlights

The quantum physics governing a chemical system is complex: each atom interacts with every other, according to various energy types: electrostatic or Coulomb, exchange and electron correlation
The purpose of the current paper is to show that the Relative Energy Gradient (REG) method is a general and powerful tool that offers insight into the local stability preference in small molecules and elucidates chemical mechanism in biomolecular active sites
SN2 reactions,[19] proton-transfer reactions,[20] intramolecular bond paths between electronegative atoms,[21] hydrogen-hydrogen interactions with respect to the torsional barrier in biphenyl,[22] short-range electrostatic potentials across torsional barriers,[23] CO2 trapping by adduct formation,[24] atom-atom repulsion as Buckingham potentials,[25] and the diastereoselective allylation of aldehydes.[26]. All these studies focused on small molecules, whereas in this paper we show how Interacting Quantum Atoms (IQA) is able to give conclusive results when applied to large biomolecules by using it in conjunction with the REG method

Summary

Introduction

The quantum physics governing a chemical system is complex: each atom interacts with every other, according to various energy types: electrostatic or Coulomb, exchange and electron correlation. From a physical point of view, kinetic energy plays a role this role is rarely discussed in chemistry textbooks, if at all. Despite this underlying physical complexity, a chemist routinely singles out a few atoms in a given system in order for them to explain the behaviour of the total system. It was shown that this explanation is not correct in work[1] that introduced the so-called secondary interaction hypothesis but later it was shown[2,3] that this hypothesis is not correct either This situation proves the need for a modern and rigorous protocol to bridge the gap between quantum mechanical data and a chemical rationale. Two questions can be posed: “which atoms are involved in determining the behaviour of a system?” and “which energy types determine the total behaviour of the system?”

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