Calibration of the dianionic phosphate group. Validation on the recognition site of the homodimeric enzyme phosphoglucose isomerase

Autor: Laurent Salmon, Marion Devillers, Jean-Philip Piquemal, Nohad Gresh
Přispěvatelé: Institut de Chimie Moléculaire et des Matériaux d'Orsay (ICCMO), Université Paris-Sud - Paris 11 (UP11), Laboratoire de chimie théorique (LCT), Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Biomedical Engineering [Austin], University of Texas at Austin [Austin]
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: Journal of Computational Chemistry
Journal of Computational Chemistry, Wiley, 2020, 41 (8), pp.839-854. ⟨10.1002/jcc.26134⟩
Wiley
ISSN: 0192-8651
1096-987X
DOI: 10.1002/jcc.26134⟩
Popis: We calibrate and validate the parameters necessary to represent the dianionic phosphate group (DPG) in molecular mechanics. DPG is an essential fragment of signaling biological molecules and protein-binding ligands. It is a constitutive fragment of biosensors, which bind to the dimer interface of phosphoglucose isomerase (PGI), an intracellular enzyme involved in sugar metabolism, as well as an extracellular protein known as autocrine motility factor (AMF) closely related to metastasis formation. Our long-term objective is to design DPG-based biosensors with enhanced affinities for AMF/PGI cancer biomarker in blood. Molecular dynamics with polarizable potentials could be used toward this aim. This requires to first evaluate the accuracy of such potentials upon representing the interactions of DPG with its PGI ligands and tightly bound water molecules. Such evaluations are done by comparisons with high-level ab initio quantum chemistry (QC) calculations. We focus on the Sum of Interactions Between Fragments Ab initio computed (SIBFA) polarizable molecular mechanics procedure. We present first the results of the DPG calibration. This is followed by comparisons between ΔE(SIBFA) and ΔE(QC) regarding bi-molecular complexes of DPG with the main-chain and side-chain PGI residues, which bind to it in the recognition site. We then consider DPG complexes with an increasing number of PGI residues. The largest QC complexes encompass the entirety of the recognition site, with six structural water molecules totaling up to 211 atoms. A persistent and satisfactory agreement could be shown between ΔE(SIBFA) and ΔE(QC). These validations constitute an essential first step toward large-scale molecular dynamics simulations of DPG-based biosensors bound at the PGI dimer interface. © 2020 Wiley Periodicals, Inc.
Databáze: OpenAIRE
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