Journal of Chemical Theory and Computation最新文献

{"title":"Ensemble-Based Precision Refinement of All-Atom Nucleic Acid Force Fields Guided by NMR NOE Pair-Distance Measurements.","authors":"Hyeonjun Kim,Youngshang Pak","doi":"10.1021/acs.jctc.5c01075","DOIUrl":"https://doi.org/10.1021/acs.jctc.5c01075","url":null,"abstract":"Accurately modeling nucleic acid structure and dynamics remains challenging for all-atom simulations, especially for noncanonical motifs such as small loops and G-quadruplexes. Despite these advances, current all-atom classical force fields often fail to reproduce ensembles consistent with high-resolution experimental data. We present a systematic refinement strategy for AMBER-based force fields that incorporates nuclear Overhauser effect distance data from NMR experiments within an ensemble-averaged optimization framework. By selectively tuning van der Waals interaction pairs, this approach markedly reduces simulation-experiment discrepancies, removes persistent artifacts, and generates free energy landscapes that better reflect experimental observations. We demonstrate broad applicability across diverse DNA and RNA systems including flexible loops and G-quadruplexes. Overall, this transferable strategy significantly improves structural accuracy and predictive power, enabling more reliable modeling of complex nucleic acid conformational ensembles.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"45 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Scoring Function for Monolayer-Protected Gold Nanoparticles Capable of Recognizing Small Organic Molecules in Solution.","authors":"Joseph Wallace,Laura Riccardi,Fabrizio Mancin,Marco De Vivo","doi":"10.1021/acs.jctc.5c01278","DOIUrl":"https://doi.org/10.1021/acs.jctc.5c01278","url":null,"abstract":"Ligand-coated gold nanoparticles (AuNPs) can act as self-organized nanoreceptors capable of selectively recognizing small organic molecules (analytes) in solution. This ability can be applied in several fields, with NMR chemosensing being a notable example. To advance the rational design of such AuNP-based nanosensors, we present a data-driven scoring function to rapidly estimate AuNP-analyte binding affinities, thus allowing fast in silico prescreening of ligand-coated AuNP sensors. This scoring function implements chemical similarity, hydrophobicity, and charge complementarity as key molecular descriptors, demonstrating excellent predictive accuracy when validated against experimental data (R2 = 0.85, MAE = 0.45 kcal/mol). Enhanced sampling molecular dynamics on representative systems revealed that ligand flexibility, monolayer packing, and hydrogen bonding critically shape binding interactions, particularly for weak binding systems. Together, these data-driven and atomistic insights offer a robust framework for the rational design and optimization of AuNP-based nanosensors.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"19 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MPBuild: An Automated Pipeline for High-Fidelity Membrane Protein Simulation System Construction.","authors":"Qing Liu,Wei Ding,Xiaojun Yao,Shenglong Ling,Changlin Tian","doi":"10.1021/acs.jctc.5c01078","DOIUrl":"https://doi.org/10.1021/acs.jctc.5c01078","url":null,"abstract":"Membrane proteins serve as the targets for 50% of FDA-approved drugs, but their dynamic characterization via molecular dynamics simulation is hindered by labor-intensive system preparation. To address this challenge, we developed MPBuild─an automated pipeline integrating structural repair, noncanonical component parametrization, and system assembly. Key innovations include (i) template-guided restoration of wild-type sequences and missing domains, (ii) automated force field generation for complex ligands, and (iii) decomposed PDB outputs enabling minute-scale system rebuilding. Benchmarked across 11 diverse membrane protein systems, MPBuild achieved processing times comparable to those of CHARMM-GUI when structural repair durations were excluded. Case studies validated the biophysical accuracy: Reproduced binding interfaces of GPR68-Gq; accurately captured SSTR2/5 and octreotide interactions, and suggested potential novel motifs that may underlie receptor subtype selectivity. In summary, MPBuild serves as a powerful tool for high-throughput membrane protein drug discovery, offering an end-to-end solution that streamlines the entire process from system preparation to simulation.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"109 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Defect-Driven Polaron Localization in π-Conjugated Systems: The Role of Spatial Correlation and Coulomb Binding.","authors":"Abhradeep Sarkar, Amiya Paul, Raja Ghosh","doi":"10.1021/acs.jctc.5c01418","DOIUrl":"https://doi.org/10.1021/acs.jctc.5c01418","url":null,"abstract":"<p><p>Defect engineering offers a powerful strategy to modulate polaron delocalization in π-conjugated materials; however, the complex interplay between different types of defects and dopant-induced Coulomb binding remains insufficiently understood. Here, we present a comprehensive theoretical investigation of hole-polaron transport using a Holstein-style Hamiltonian applied to π-conjugated lattices such as polymers and covalent organic frameworks (COFs) that incorporate vacancy and linker defects, a disorder framework encompassing distributions of disordered sites, and dopant-induced Coulomb binding effects. Simulated mid-infrared signatures and polaron coherence numbers uncover distinct and nuanced behaviors, revealing how the spatial correlation (random vs correlated) of different defect types governs polaron delocalization pathways. While dopant counterions strongly localize polarons, their precise positioning relative to crystalline versus disordered domains critically modulates transport efficiency. To establish experimental relevance, we compare our simulations with polarized intrachain and interchain mid-infrared spectra of doped P3HT films, providing fundamental insights into how specific dopant-polymer configurations give rise to anisotropic spectroscopic signatures and their direct correlation with anisotropic polaron transport. The strong agreement between theory and experiment validates our predictions and establishes guiding principles for optimizing polaron transport in disordered π-conjugated materials.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145342105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing Computational Strategies for the Evaluation of Antibody Binding Affinities.","authors":"Ida Autiero,Damiano Buratto,Fengyi Guo,Wanding Wang,Malay Ranjan Biswal,Kevin C Chan,Ruhong Zhou,Francesco Zonta","doi":"10.1021/acs.jctc.5c01231","DOIUrl":"https://doi.org/10.1021/acs.jctc.5c01231","url":null,"abstract":"Accurate evaluation of binding affinity is critical in drug discovery to identify molecules that bind strongly to their targets while minimizing off-target effects. Although binding affinity calculations are theoretically well defined, they require exhaustive sampling of configurational space, a step that often requires significant computational resources. In this study, we compare different methods for calculating the binding energy of antibodies targeting a peptide derived from the N-terminus of CXCR2, a GPCR-family protein. Contrary to some previous reports, we find that equilibrium molecular mechanics Poisson-Boltzmann surface area (MMPBSA) calculations yield better agreement with experimental binding affinities than nonequilibrium potential of mean force evaluations, underscoring the system-dependent performance of these methods. We also observed a modest improvement in accuracy when MMPBSA is combined with replica exchange molecular dynamics, albeit at a significantly higher computational cost. Calculation based on the Rosetta force field, instead, produced results that did not correlate with the experimental data. We attribute these findings to two factors, which could limit the applicability of some methodologies that are widely used in computing the binding energy: the high potency of the antibodies studied and the dominance of hydrophobic interactions between the antibodies and the peptide. Overall, this work provides important insights for optimizing in silico antibody screening strategies.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"127 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Knowles Partitioning from a Stationary Condition: Single- and Multireference Case.","authors":"Ágnes Szabados, András Gombás, Péter R Surján","doi":"10.1021/acs.jctc.5c01147","DOIUrl":"https://doi.org/10.1021/acs.jctc.5c01147","url":null,"abstract":"<p><p>A stationary condition involving the first-order wave function of many-body perturbation theory (PT) is shown to lead to the partitioning introduced recently by Knowles (<i>J</i>. <i>Chem</i>. <i>Phys</i>., <i>156</i>, 011101 (<b>2022</b>)). This facilitates direct generalization for multireference (MR) PT schemes operating with a one-body Hamiltonian at zero-order. The essence of the method is an optimization of one-body integrals in the first-order interacting subspace, thereby achieving superior performance over Møller-Plesset (MP) type approaches. The stationary condition based extension, performed in the pivot-independent variant of the multiconfiguration PT (frame MCPT, fMCPT), rectifies the shortcomings of our previous MR adaptation. The resulting PT series comes close to the stationary condition-based extension, carried out in the complete active space PT (CASPT) formalism. Numerical results demonstrate that Knowles partitioning consistently outperforms MP partitioning in fMCPT.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145342106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Capturing Electron Correlation with Machine Learning through a Data-Driven CASPT2 Framework.","authors":"Grier M Jones, Konstantinos D Vogiatzis","doi":"10.1021/acs.jctc.5c01333","DOIUrl":"https://doi.org/10.1021/acs.jctc.5c01333","url":null,"abstract":"<p><p>Multireference perturbation theory methods, such as complete active space second-order perturbation theory (CASPT2), are often employed to recover the missing electron correlation from multiconfigurational zeroth-order wave functions. Here, we introduce the data-driven CASPT2 (DDCASPT2) method to capture dynamic electron correlation using features generated from lower-level electronic structure methods, such as Hartree-Fock and complete active space self-consistent field (CASSCF) theory. We examine the effects of system size, basis set size, and the number of two-electron excitations using a small, but diverse, set of molecules. We also provide insights into our physics-based feature set using SHapley Additive exPlanation (SHAP) analysis, a feature analysis method based on cooperative game theory. In this paper, we utilize these insights to introduce a DDCASPT2 method, which provides a machine-learning-based alternative to traditional single- and multistate CASPT2 for capturing dynamical electron correlation with near-CASPT2 quality accuracy.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145342104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"One Basis Set to Rule Them All: Toward an Affordable Platinum Standard via Natural Orbital Thresholds.","authors":"Silvia Di Grande,Mihály Kállay,Vincenzo Barone","doi":"10.1021/acs.jctc.5c01424","DOIUrl":"https://doi.org/10.1021/acs.jctc.5c01424","url":null,"abstract":"We propose a strategy to mitigate the prohibitive cost of coupled cluster methods, including up to quadruple or pentuple excitations, often referred to as the platinum standard, by combining a single sufficiently large basis set with frozen natural orbitals. In our framework, natural orbitals are generated from low-order perturbative or coupled cluster density matrices, truncated according to an occupation threshold, and recanonicalized to yield correlated orbitals fully compatible with standard coupled cluster algorithms. Using occupation thresholds rather than fixed-percentage truncations preserves the size consistency and enables systematic accuracy control. Benchmarks on standard data sets and challenging molecular systems show that large basis sets with aggressively reduced numbers of correlated orbitals consistently outperform smaller basis sets with the same number of correlated orbitals. These results support a unified workflow in which a single basis set is retained for all excitation levels with progressively larger thresholds to reduce the virtual space. Although optimal thresholds are not yet predefined, this framework paves the way toward unsupervised protocols aimed at approaching platinum standard accuracy for unprecedented system sizes at nonprohibitive cost.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"41 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145331824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of Strong-Correlation Corrected Range-Separated Local Hybrid Functionals for Metalloenzyme Reactions.","authors":"Andrew M M Kai, Tiffany T Nguyen, Robin Grotjahn","doi":"10.1021/acs.jctc.5c01430","DOIUrl":"https://doi.org/10.1021/acs.jctc.5c01430","url":null,"abstract":"<p><p>Accurately modeling the complex electronic structure of metalloenzyme active sites remains a significant challenge for density functional theory (DFT). The MME55 test set [<i>J. Chem. Theory Comput.</i> <b>2023</b>, <i>19</i>, 8365] is a recent benchmark providing high-level DLPNO-CCSD(T)/CBS reference values for large, practically relevant metalloenzyme models with up to 116 atoms. So far, the best-performing rung-4 hybrids were MPW1B95-D3(BJ) with a mean absolute error (MAE) of 2.67 kcal/mol and ωB97M-V (2.78 kcal/mol). This work focuses on range-separated local hybrids (RSLHs), a recent class of rung-4 functionals that use both a real-space dependent and interelectronic distance dependent admixture of exact (Hartree-Fock-like) exchange. Strong-correlation corrected RSLHs (scRSLHs) based on real-space nondynamical correlation models are also assessed. The best-performing functional is the scRSLH ωLH23tdB-D4 with an MAE of 2.46 kcal/mol. Overall, the results reflect a systematic improvement in accuracy along the functional development series from LH to RSLH to scRSLH. However, our analysis also indicates that the real-space nondynamical correlation model is not the primary driver of this improvement, which is instead dominated by other features of the functional design. Additionally, we studied (sc)(RS)LHs for the ENZYMES22 set of enzyme reactions comprising metal-free active site models as well as the ECR20 benchmark of net reaction energies of enzyme-catalyzed reactions. MAEs of 1.45 and 0.63 kcal/mol confirm ωLH23tdB-D4 as one of the top-performing functionals for these sets. Due to inaccuracies in the original CCSD(T)/aug-cc-pVDZ + [SCS-MP2/aug-cc-pVTZ - SCS-MP2/aug-cc-pVDZ] reference values for the ECR20 set, we devise new canonical CCSD(T)/CBS reference values using an aug-cc-pVXZ (X = D, T, Q)-based basis set extrapolation. Because scRSLHs have only very recently emerged, this benchmark study is accompanied by critical assessments of their use as a practical tool. We analyze the grid dependence of their seminumerical implementation in Turbomole and evaluate the computational cost and parallel scaling on a shared-memory OpenMP architecture using up to 192 physical CPU cores.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145336009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficient Subsystem TDDFT Calculations for Optical Rotatory Dispersion of Molecules in Solution: Converging the Configurational Averaging for Norbornenone in Acetonitrile.","authors":"Sakyo Ochi,Niklas Niemeyer,Diddo Diddens,Johannes Neugebauer","doi":"10.1021/acs.jctc.5c01074","DOIUrl":"https://doi.org/10.1021/acs.jctc.5c01074","url":null,"abstract":"We present a comprehensive study on optical rotatory dispersion (ORD) calculations for a chiral molecule in solution by means of subsystem TDDFT (sTDDFT) for snapshots extracted from classical molecular dynamics (MD) trajectories. As a prototypical example, we study the ORD of norbornenone in acetonitrile. Uncovering the microscopic origin of the solvent effect on the ORD necessitates an explicit quantum chemical solvation model and robust configurational sampling, rendering such calculations computationally extremely heavy. Here, we employ sTDDFT to study the convergence of the ORD signal with respect to both the size of the solvation shell considered and the number of snapshots considered in the configurational sampling, as well as the interdependence of these two factors. We demonstrate that several thousand snapshots have to be considered to accurately converge the solvation effect even for comparatively small solvated clusters. By systematically studying solvent cages of increasing size, we observe a clear correlation between the radial distribution function of acetonitrile around norbornenone and the ORD dependence on the solvent-shell size. Larger solvation shells, unfortunately, usually also require more extensive configurational sampling. To facilitate such an averaging procedure on a quantum chemical basis, we introduce further algorithmic improvements to achieve an additional speed up in our sTDDFT calculations. We observe that sTDDFT accurately captures the qualitative features of the solvation-shell size dependence. In addition, a systematic empirical correction is developed to achieve quantitative agreement with the parent TDDFT results. Overall, sTDDFT in combination with classical MD for snapshot generation offers an economical approach toward obtaining converged ORD results in solution.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"1 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145331826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}