Quick-and-Easy Validation of Protein–Ligand Binding Models Using Fragment-Based Semiempirical Quantum Chemistry

Journal of Chemical Information and Modeling, Год журнала: 2025, Номер unknown

Опубликована: Янв. 3, 2025

Electronic structure calculations in enzymes converge very slowly with respect to the size of model region that is described using quantum mechanics (QM), requiring hundreds atoms obtain converged results and exhibiting substantial sensitivity (at least smaller models) which amino acids are included QM region. As such, there considerable interest developing automated procedures construct a based on well-defined criteria. However, testing such burdensome due cost large-scale electronic calculations. Here, we show semiempirical methods can be used as alternatives density functional theory (DFT) assess convergence sequences models generated by various protocols. The these tests reduced even further means many-body expansion. We use this approach examine (with size) protein–ligand binding energies. Fragment-based afford well-converged interaction energies tiny fraction required for DFT Two-body interactions between ligand single-residue acid fragments low-cost way "QM-informed" enzyme size, furnishing an automatable active-site model-building procedure. This provides streamlined, user-friendly constructing binding-site requires neither priori information nor manual adjustments. Extension thermochemical should straightforward.

Язык: Английский

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Testing a Heterogeneous Polarizable Continuum Model against Exact Poisson Boundary Conditions

Journal of Chemical Theory and Computation, Год журнала: 2025, Номер unknown

Опубликована: Фев. 17, 2025

The polarizable continuum model (PCM) is a computationally efficient way to incorporate dielectric boundary conditions into electronic structure calculations, via boundary-element reformulation of Poisson's equation. This transformation only rigorously valid for an isotropic medium. To simulate anisotropic solvation, as encountered at interface or when parts system are solvent-exposed while other in nonpolar environment, ad hoc modifications the PCM formalism have been suggested, which constant assigned separately each atomic sphere that contributes solute cavity. accuracy this "heterogeneous" (HetPCM) method tested here first time, by comparison results from generalized Poisson equation solver. latter more expensive and cumbersome approach arbitrary conditions, but one corresponds well-defined scalar permittivity function, ε(r). We examine simple systems function ε(r) can be constructed manner maps reasonably well onto sphere, using εsolv = 78 range smaller values represent hydrophobic environments. For constants εnonp ≤ 2, differences between HetPCM solvation energies large compared effect anisotropy on energy. 4 10, however, agree within 2 kcal/mol most cases. As realistic use case, we apply predict pKa blue copper proteins. affords line with experimental either gas-phase calculations homogeneous (isotropic) results.

Язык: Английский

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Untangling Sources of Error in the Density-Functional Many-Body Expansion

The Journal of Physical Chemistry Letters, Год журнала: 2025, Номер unknown, С. 2793 - 2799

Опубликована: Март 7, 2025

The many-body expansion provides a framework for data-driven applications of electronic structure theory, including parametrization classical force fields and machine learning. However, we demonstrate that its use significantly amplifies quadrature grid errors when modern density-functional approximations are employed. Standard grids work well in conventional calculations result runaway error accumulation used with the expansion. At same time, delocalization is also exacerbated, leading to exaggerated estimates nonadditive n-body interactions. This illustrated anion–water clusters using SCAN, r2SCAN, ωB97X-V ωB97M-V functionals. By employing dense grids, inherent self-interaction exposed, which can then be mitigated variety other strategies.

Язык: Английский

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Efficient Computational Strategies of the Cluster-in-Molecule Local Correlation Approach for Interaction Energies of Large Host–Guest Systems

Journal of Chemical Theory and Computation, Год журнала: 2025, Номер unknown

Опубликована: Март 7, 2025

We propose a heterogeneously accelerated reduced cluster-in-molecule (CIM) local correlation approach for calculating host-guest interaction energies. The essence of this method is to compute only the clusters that make significant contributions energies while approximately neglecting those with smaller contributions. Benchmark calculations at CIM resolution-of-identity second-order Mo̷ller-Plesset perturbation (CIM-RI-MP2) or spin-component-scaled RI-MP2 (CIM-SCS-RI-MP2) levels, involving three medium-sized protein-ligand structures, demonstrate achieves over 48% time savings without compromising accuracy, as energy error remains within 0.5 kcal/mol compared full method. To further enhance cluster computation efficiency, we developed heterogeneous parallel version CIM-(SCS-)RI-MP2 It 93% internode efficiency and 98% multi-GPU card tested large complexes. Ultimately, hardware-accelerated applied calculate six systems, ranging from 913 1425 atoms. Remarkably, requires 4.3-22.8% achieve accurate results, under condition using single node, wall 2 days. Additionally, domain-based pair natural orbital coupled singles, doubles, perturbative triples [CIM-DLPNO-CCSD(T)] successfully calculation 1425-atom system. These computations capability specific electronic structure accurately systems.

Язык: Английский

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Analyzing Many‐Body Charge Transfer Effects With the Fragment Molecular Orbital Method

Journal of Computational Chemistry, Год журнала: 2025, Номер 46(13)

Опубликована: Май 15, 2025

ABSTRACT A many‐body expansion of charge transfer (CT) energies is developed for the fragment molecular orbital method. It applied to decouple CT and mix terms in interaction energy decomposition analyses. Many‐body graphically illustrated form frontier diagrams. The contribution interactions elucidated application method water clusters, solvated ions, polypeptide motifs.

Язык: Английский

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