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

Abstract

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. WWW.C-CHEM.ORG J. Comput. Chem. 2020, 41, 839-854 WWW.CHEMISTRYVIEWS.COM 105 to 225 , at fixed θ angle of 270 . Points 29-35 (E): 30 variations of the O-P-O 2 -H angle, from 0 to 180 , at fixed θ angle of 225 . Points 36-42 (F): 30 variations of the O─P─O 2 ─H angle, from 0 to 180 , at fixed θ angle of 255 . Points 43-49 (G): 30 variations of the O─P─O 3 ─H angle, from 0 to 180 , at fixed θ angle of 225 . Points 50-56 (H): 30 variations of the O─P─O 3 ─H angle, from 0 to 180 , at fixed θ angle of 255 . [Color figure can be viewed at wileyonlinelibrary.com] WWW.C-CHEM.ORG

Multimolecular complexes of the phosphodiester anion with Zn(II) or Mg(II) and water molecules—Preliminary validations of a polarizable potential by ab initio quantum chemistry

“…Further refinements could be sought. Thus E MTP * could be possibly improved if, as mentioned in Devillers et al 39 a greater weight than is presently the case were conferred to the charge‐quadrupole component of the penetration, which depends upon a general coefficient intervening in the exponential of this component independent of the effective atomic radii for E pen . This has been done, in the context of SAPT analyses for water calibration at the correlated level 60 .…”

“…51 We have resorted to the first two functionals consistent with previous SIBFA validation studies on multimolecular complexes. 32,[38][39][40][41] The choice of the ω-B97XD functional was motivated by a recent study SAPT-DFT study 52 on the complexes of water with Zn(II) and F À which showed this functional to be the one enabling the closest agreement to SAPT-DFT. The BSSE 53 correction was applied to all QC calculations.…”

Development of the Quantum Inspired SIBFA Many-Body Polarizable Force Field: Enabling Condensed Phase Molecular Dynamics Simulations

“…This work opens a new avenue for condensed phase simulations of complex systems as both the non-additivity and the non-isotropy of the SIBFA potential were amply validated in numerous previous studies from our Laboratories. 2,[76][77][78][79][80][81][82][83][84][85] This should ensure for a safe transferability, from the training set data to proteins and nucleic acids. At this stage, it is important to note that the simple AMOEBA intramolecular potential used in this study is not optimal since its ideal bond angle was set to 108.5 • .…”

Intermolecular interactions of the extended recognition site of VIM‐2 metallo‐β‐lactamase with 1,2,4‐triazole‐3‐thione inhibitors. Validations of a polarizable molecular mechanics potential by ab initio QC

“…In order to ensure better control of the nonadditivity of E pol , we have included in the optimization procedure the 10 complexes of TZT with the monozinc cores, that is, each of the His3 and Asp-Cys-His cores in their structures extracted from their complexes with each of the five inhibitors. As in previous studies, 33,64 we have similarly resorted to a Zn(II) "probe" to maximize the response of the probed ligands regarding both first-order (Coulomb and exchange), and second-order (polarization and charge-transfer) responses. Thus, benzocarboxylate was probed by Zn(II) approaching one anionic carboxylate upon performing in-plane radial and angular variations, and radial variations along a perpendicular to the plane passing through this oxygen, or to the extracyclic C atom or the C atoms ortho, para or meta to it.…”

“…In light of the comparisons with the QC results on the extended recognition site, we sought for further refinements of the relevant parameters for TZT, for the benzocarboxylate arm (an R2 substituent in four of the five considered inhibitors), but also for imidazole, which occurs four times out of six as a Zn‐ligand in the dizinc binding core of VIM‐2. We have resorted to a procedure recently integrated into the standard SIBFA software and used to calibrate the dianionic phosphate group (DPG) 64 and to derive a water potential grounded on SAPT for MD simulations on liquid water [Naseem‐Khan et al, to be submitted]. The relevant fragment specific parameters for the SIBFA E MTP , E rep , E pol , and E ct contributions were optimized by LSQF minimization of the error with respect to their respective RVS counterparts E C , E X , E pol , and E ct as computed in all probed positions of the fragment.…”