Importance of explicit smeared lone-pairs in anisotropic polarizable molecular mechanics. Torture track angular tests for exchange-repulsion and charge transfer contributions

Khoury, Léa El; Naseem-Khan, Sehr; Kwapień, Karolina; Hobaika, Zeina; Maroun, Richard G.; Piquemal, Jean‐Philip; Gresh, Nohad

doi:10.1002/jcc.24830

Cited by 13 publications

(30 citation statements)

References 82 publications

(177 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The choice of Zn(II) as a probe, in keeping with Refs ,. was done to maximize the polarization and charge‐transfer responses of probed DPG.…”

Section: Methodsmentioning

confidence: 99%

“…The sole variables were the effective radii of the amide H and N atoms, those of carbonyl oxygen having been previously calibrated …”

Section: Methodsmentioning

confidence: 99%

“…Both N and C have two π lone pair orbitals, with starting total occupation numbers of one and of one‐half, respectively. O has two in‐plane sp 2 lone‐pairs and two “smeared” lone‐pairs on both sides of the NMF plane projecting out of the C═O bond . The total starting occupation number is four.…”

Section: Methodsmentioning

confidence: 99%

“…We next analyze the nonadditivities of DPG binding to an entity made out of two successive, covalently bound NMF fragments making up the backbones of Gly 211 and Thr 212 and the side chain of Thr 212 . It is worth mentioning that most our previous studies addressing nonadditivity had a divalent cation in the center of a polyligated complex. Thus, nonadditivity stemmed from the shielding of a dicationic charge by electron‐rich ligands.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2020

Self Cite

View full text Add to dashboard Cite

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

show abstract

“…The choice of Zn(II) as a probe, in keeping with Refs ,. was done to maximize the polarization and charge‐transfer responses of probed DPG.…”

Section: Methodsmentioning

confidence: 99%

“…The sole variables were the effective radii of the amide H and N atoms, those of carbonyl oxygen having been previously calibrated …”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…In addition to handling the halobenzene interactions [69,70], a further asset of SIBFA and related polarizable potentials [71] is the reliable handling of poly-ligated complexes of divalent cations [72] and interactions involving 'discrete' structural waters [73,74]. Such structural motives are also encountered in the intasome-INSTI complexes.…”

Section: Discussionmentioning

confidence: 99%

Untitled

Supplemental Information 3: Titration Curve of Dolutegravir

View full text Add to dashboard Cite

Three Integrase (IN) strand transfer inhibitors are in intensive clinical use, raltegravir, elvitegravir anddolutegravir. However, the onset of IN resistance mutations limits their therapeutic efficiency. As put forth earlier, the drug affinity for the intasome could be improved by targeting preferentially the retroviralnucleobases, which are little, if at all, mutation-prone. We report experimental results of anisotropy fluorescence titrations of viral DNA by these three drugs. These show that the ranking of their inhibitory activities of the intasome corresponds to that of their free energies of binding, D Gs,to retroviral DNA, and that such a ranking is only governed by the binding enthalpies, D H, the entropy undergoing marginal variations.This ranking can therefore be directly correlated to that of model Quantum Chemistry (QC) calculations of intermolecular interaction energies of the sole halobenzene ring with the highly conserved retroviral nucleobases G4 and C14, using Density Functional Theory. This DE(QC) ranking is in turn reproduced by the corresponding DE tot values computed with a polarizable molecular mechanics/dynamics procedure, SIBFA (Sum of Interactions Between Fragments Ab initio computed). Such validations should enable polarizable molecular dynamics simulations on more potent inhibitors in their complexes with the complete intasome. Such derivatives should principally encompass modified halobenzene rings.

show abstract

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

et al. 2020

Self Cite

View full text Add to dashboard Cite

Molecular dynamics on the complexes of inhibitors with Zn-metalloproteins are a privileged area of applications of polarizable molecular mechanics potentials. With which accuracy could these reproduce the QC intermolecular interaction energies in the two mono-zinc cores and in the dizinc core, toward full-fledged MD simulations on the entire protein complexes? We considered the complexes of the extended recognition site of a Zn-dependent metallo-β-lactamase, VIM-2, produced by bacteria responsible for nosocomial infections, with five newly synthesized inhibitors sharing an original dizinc binding group, 1,2,4-triazole-3-thione (TZT). We considered the energy-minimized structures of each of the five VIM-2 complexes obtained with the SIBFA potential. Energy decomposition analyses (EDA) at the HF level enabled to compare the QC and the SIBFA ΔE values and their contributions in the zinc cores, with and without TZT, totaling 30 complexes. With one exception, the ΔE(QC) values were reproduced with relative errors <1.5%. We next considered the complex of the entire inhibitors with an extended model of VIM-2 recognition site, totaling up to 280 atoms. ΔE(SIBFA) could closely reproduce ΔE(QC). EDA analyses were resumed on the complexes of each inhibitor arm with its interacting VIM-2 residues. As a last step, EDA results at correlated levels were analyzed for the mono-and dizinc sites enabling comparisons with dispersion-augmented ΔE(SIBFA) and correlated multipoles and polarizabilities. Closely reproducing ΔE(QC) and the contrasting trends of its individual contributions should enable for dependable free energy perturbation studies and comparisons to recent experimental ΔG values, limiting as much as possible the reliance on error compensations.

show abstract

Importance of explicit smeared lone-pairs in anisotropic polarizable molecular mechanics. Torture track angular tests for exchange-repulsion and charge transfer contributions

Cited by 13 publications

References 82 publications

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

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

Untitled

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

Contact Info

Product

Resources

About