arXiv subjects

Nohad Gresh

Publications and source records attributed to Nohad Gresh.

5 recordsLinked to original sources

arXiv2026

Probing Extended Recognition Sites in Zn-Metalloproteins via Quantum Chemistry and Polarizable Molecular Dynamics

Zn-metalloproteins play vital roles in numerous metabolic processes, making them high-value targets for structure-based drug design. To advance these efforts, it is useful to unravel the individual components of the intermolecular interaction energies (DE) that stabilize the Znbinding cavity, both in the absence and presence of bound protein ligands. Here, we utilize quantum chemistry (QC) to decompose DE into distinct physical contributions. The relative magnitudes of these components vary significantly depending on the coordination number (four to six) and the chemical nature ('hard' vs. 'soft') of the Zn-coordinating ligands. These high-level QC analyses serve to calibrate and validate polarizable molecular mechanics potentials, effectively extending the accurate description of electronic effects beyond the immediate Zn-binding cavity to enlarged recognition sites and, ultimately, entire protein systems over long molecular dynamics (MD) simulation timescales. Following a concise overview of our QC methodology, we present validation studies on complexes containing up to 300 atoms and discuss the prospects of applying this framework to large-scale simulations of Zn-metalloprotein-ligand complexes. Finally, the structural and energetic role of discrete, highly polarizable water molecules is highlighted.

physics.chem-ph↗

arXiv2022

Targeting the Major Groove of the Palindromic d(GGCGCC)2 Sequence by Oligopeptide Derivatives of Anthraquinone Intercalators

GC-rich sequences are recurring motifs in oncogenes and retroviruses, and could be targeted by non-covalent major-groove therapeutic ligands. We considered the palindromic sequence d(G1G2C3G4C5C6)2, and designed several oligopeptide derivatives of the anti-cancer intercalator mitoxantrone. The stability of their complexes with a 18-mer oligonucleotide encompassing this sequence in its center was validated using polarizable molecular dynamics. We report the most salient structural features of two novel compounds, having a dialkylammonium group as a side-chain on both arms. The anthraquinone ring is intercalated in the central d(CpG)2 sequence with its long axis perpendicular to that of the two base-pairs. On each strand, this enables each ammonium group to bind in-register to O6/N7 of the two facing G bases upstream. We subsequently designed tris-intercalating derivatives, each dialkylammonium substituted with a connector to an N9-aminoacridine intercalator extending our target range from six- to a ten-base pair palindromic sequence, d(C1G2G3G4C5G6C7C8C9G10)2. The structural features of the complex of the most promising derivative are reported. The present design strategy paves the way for designing intercalator-oligopeptide derivatives with an even higher selectivity, targeting an increased number of DNA bases, going beyond ten.

physics.chem-ph↗

arXiv2022

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

We present the extension of the SIBFA (Sum of Interactions Between Fragments Ab initio Computed many-body polarizable force field to condensed phase Molecular Dynamics (MD) simulations. The Quantum-Inspired SIBFA procedure is grounded on simplified integrals obtained from localized molecular orbital theory and achieves full separability of its intermolecular potential. It embodies long-range multipolar electrostatics (up to quadrupole) coupled to a short-range penetration correction (up to charge-quadrupole), exchange-repulsion, many-body polarization, many-body charge transfer/delocalization, exchange-dispersion and dispersion (up to C10). This enables the reproduction of all energy contributions of ab initio Symmetry-Adapted Perturbation Theory (SAPT(DFT)) gas phase reference computations. The SIBFA approach has been integrated within the Tinker-HP massively parallel MD package. To do so all SIBFA energy gradients have been derived and the approach has been extended to enable periodic boundary conditions simulations using Smooth Particle Mesh Ewald. This novel implementation also notably includes a computationally tractable simplification of the many-body charge transfer/delocalization contribution. As a proof of concept, we perform a first computational experiment defining a water model fitted on a limited set of (SAPT(DFT)) data. SIBFA is shown to enable a satisfactory reproduction of both gas phase energetic contributions and condensed phase properties highlighting the importance of its physically-motivated functional form.

physics.chem-ph↗

arXiv2021

Assessment of SAPT and Supermolecular EDAs Approaches for the Development of Separable and Polarizable force fields

What is the best reference quantum chemical approach to decipher the energycomponents of the total interaction energy : Symmetry-Adapted Perturbation Theory(SAPT) or Supermolecular Energy Decomposition Analysis (EDA) methods? With the rise of physically motivated polarizable force fields (polFF) grounded on these procedures, the need to answer such a question becomes critical. these procedures, the need to answer such a question becomes critical. We report a systematic and detailed assessment of three variants of SAPT (namely SAPT(2), SAPT(2+3) and SAPT(DFT) and three supermolecular EDAs approaches (ALMO, CSOV and RVS). A set of challenging, strongly bound water complexes: (H2O)2, (Zn2+)H2O and F-)H2O are used as stress-tests for these electronic structure methods. We have developed a procedure to separate the induction energy into the polarization and charge-delocalization using an infinite-order strategy based on SAPT(DFT). This paper aims to provide an overview of the capabilities and limitations, but also similarities, of SAPT and supermolecular EDAs approaches for polFF developments. Our results show that SAPT(DFT)/noS**2 and ωB97X-D||ALMO are the most accurate and reliable techniques

physics.chem-ph↗

arXiv2020

Quantum-Chemistry based design of halobenzene derivatives with augmented affinities for the HIV-1 viral G4/C16 base-pair

The HIV-1 integrase (IN) is a major target for the design of novel anti-HIV inhibitors. Among these, three inhibitors which embody a halobenzene ring derivative (HR) in their structures are presently used in clinics. High-resolution X-ray crystallography of the complexes of the IN-viral DNA transient complex bound to each of the three inhibitors showed in all cases the HR ring to interact within a confined zone of the viral DNA. The extension of its extracyclic CX bond is electron-depleted, owing to the existence of the "sigma-hole". It interacts favorably with the electron-rich rings of base G4. We have sought to increase the affinity of HR derivatives for the G4/C16 base pair. We thus designed thirteen novel derivatives and computed their Quantum Chemistry (QC) intermolecular interaction energies (delta(E)) with this base-pair. Most compounds had DE values significantly more favorable than those of the HR of the most potent halobenzene drug presently used in clinics, Dolutegravir. This should enable the improvement in a modular piece-wise fashion, the affinities of halogenated inhibitors for viral DNA (vDNA). In view of large scale polarizable molecular dynamics simulations on the entirety of the IN-vDNA-inhibitor complexes, validations of the SIBFA polarizable method are also reported, in which the evolution of each delta(SIBFA) contribution is compared to its QC counterpart along this series of derivatives.

physics.chem-ph↗