Journal of Chemical Theory and Computation最新文献

{"title":"Conformational Analysis of Macrocyclic Compounds Using a Machine-Learned Interatomic Potential.","authors":"Hani M Hashim, Jeremy N Harvey","doi":"10.1021/acs.jctc.5c01072","DOIUrl":"https://doi.org/10.1021/acs.jctc.5c01072","url":null,"abstract":"<p><p>Macrocyclic compounds play a vital role in many chemical and biological systems, yet their conformational analysis remains a significant challenge. In this work, we investigate the conformational landscape of macrocyclic compounds using a machine-learned interatomic potential (MLIP) based on a Nequip-like graph neural network. This MLIP is trained on the energy differences between ωB97XD3 and GFN1-xTB. The model not only reproduces the DFT relative conformer energies of the macrocycles with high fidelity but also yields optimized structures that are practically identical to those obtained via density functional theory. Furthermore, when integrated into a metadynamics-based conformational sampling framework (CREST), we recover structures that very closely match the structure obtained after gas-phase optimization with DFT starting from the crystal structure. These results underscore the potential of machine learning to overcome longstanding challenges in the conformational analysis of complex macrocyclic systems.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145298010","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":"Density-Functionalized QM/MM Delivers Chemical Accuracy For Solvated Systems.","authors":"Xin Chen, Jessica A Martinez B, Xuecheng Shao, Marc Riera Riambau, Oliviero Andreussi, Francesco Paesani, Michele Pavanello","doi":"10.1021/acs.jctc.5c01440","DOIUrl":"https://doi.org/10.1021/acs.jctc.5c01440","url":null,"abstract":"<p><p>We present a reformulation of QM/MM as a fully quantum mechanical theory of interacting subsystems, all treated at the level of density functional theory (DFT). For the MM subsystem, which lacks orbitals, we assign an ad hoc electron density and apply orbital-free DFT functionals to describe its quantum properties. The interaction between the QM and MM subsystems is also treated using orbital-free density functionals, accounting for Coulomb interactions, exchange, correlation, and Pauli repulsion. Consistency across QM and MM subsystems is ensured by employing data-driven, many-body MM force fields that faithfully represent DFT functionals. Applications to water-solvated systems demonstrate that this approach achieves unprecedented, very rapid convergence to chemical accuracy as the size of the QM subsystem increases. We validate the method with several pilot studies, including water bulk, water clusters (prism hexamer and pentamers), solvated glucose, a palladium aqua ion, and a wet monolayer of MoS₂.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145290335","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":"Similarity Constrained CC2: Toward Efficient Coupled Cluster Nonadiabatic Dynamics among Excited States.","authors":"Leo Stoll,Sara Angelico,Eirik F Kjønstad,Henrik Koch","doi":"10.1021/acs.jctc.5c00997","DOIUrl":"https://doi.org/10.1021/acs.jctc.5c00997","url":null,"abstract":"Despite their high accuracy, standard coupled cluster models cannot be used for nonadiabatic molecular dynamics simulations because they yield unphysical complex excitation energies at conical intersections between same symmetry excited states. On the other hand, similarity constrained coupled cluster theory has enabled the application of coupled cluster theory in such dynamics simulations. Here, we present a similarity constrained perturbative doubles (SCC2) model with same symmetry excited-state conical intersections that exhibit correct topography, topology, and real excitation energies. This is achieved while retaining the favorable computational scaling of the standard CC2 model. We illustrate the model for conical intersections in hypofluorous acid and thymine, and compare its performance with other methods. The results demonstrate that conical intersections between excited states can be described correctly and efficiently at the SCC2 level. We therefore expect that the SCC2 model will enable coupled cluster nonadiabatic dynamics simulations for large molecular systems.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"11 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145296265","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":"Black-Box Simulations of Anharmonic Vibrational Chiroptical Spectra: Problems with Property Third Derivatives and the Solvent.","authors":"Qin Yang,Valery Andrushchenko,Jana Hudecová,Josef Kapitán,Julien Bloino,Isabelle Bowker,Petr Bouř","doi":"10.1021/acs.jctc.5c01132","DOIUrl":"https://doi.org/10.1021/acs.jctc.5c01132","url":null,"abstract":"Chiroptical methods, including vibrational circular dichroism (VCD) and Raman optical activity (ROA), reveal details about molecular structure. For three model molecules, α-pinene, camphor, and fenchone, we show that increased sensitivity of modern spectrometers makes it possible to record even fine spectral features, such as overtone and combination bands. However, understanding, interpretation, and simulation of them require relatively expensive computations, going beyond the harmonic approximation. For this purpose, vibrational perturbation theory at the second order (VPT2) has proven to provide an excellent price-performance balance. As it becomes more common, inconsistencies in electronic structure calculations, hidden by error compensation at the harmonic level, emerge. In particular, while trying to interpret the spectra, we found that the commonly used polarizable continuum models (PCM) of solvent may introduce erroneous perturbations to the higher derivatives of dipole moments and polarizabilities needed to simulate spectral intensities. We therefore analyze the experimental spectra on the basis of the simulations and explore parameters allowing for a \"black-box\" VPT2 application. In particular, explicit cavities used for the hydrogen atoms resulted in excessively large third derivatives of molecular polarizabilities and sometimes led to incorrect signs of ROA and VCD bands, even for fundamental transitions. This could be partially rectified by a combination of different approximation levels used for the calculation of different properties, or by using PCM cavities not explicitly adapted for hydrogen atoms. Under these conditions, VPT2 combined with a proper treatment of resonances appears as an excellent tool to simulate and understand the spectra, including the assignment of weak anharmonic bands.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"6 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145277179","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":"Benchmarking Alchemical Relative Binding Free Energy Calculations for Nucleotide Binding to Multimeric ATPases.","authors":"Apoorva Purohit,Xiaolin Cheng","doi":"10.1021/acs.jctc.5c01069","DOIUrl":"https://doi.org/10.1021/acs.jctc.5c01069","url":null,"abstract":"Multimeric ATPases generally bind nucleotides at intersubunit interfaces, where cooperative or allosteric interactions complicate experimental measurement of binding affinities. Here, we present a large-scale benchmarking study of alchemical relative binding free energy (RBFE) calculations using fixed-charge force fields across six classes of oligomeric ATPases: F1-ATPase, MalK, MCM, Rho, FtsK, and gp16. While previous absolute or relative binding free energy studies have largely focused on monomeric or single-site ATPases, this work extends RBFE calculations to 55 interfacial binding sites in multimeric ATPases, providing insight into the successes and limitations of alchemical free energy methods in complex, cooperative systems. RBFE simulations were conducted both in the presence and absence of the central substrate (DNA or RNA) to assess its impact on nucleotide-binding free energies. The highly charged and conformationally flexible nature of nucleotide ligands necessitated extensive sampling (>20 ns per alchemical window) to account for slow relaxation associated with long-range electrostatic interactions. Our RBFE results reproduced experimentally observed binding preferences for 91% of the sites in F1-ATPase, MalK, and MCM ATPases, which exhibited low global and local structural deviations during simulations across alchemical windows. In contrast, only 60% agreement was observed for Rho, FtsK, and gp16─systems with greater structural variability. This study not only highlights the predictive potential of alchemical free energy methods for nucleotide binding in protein complexes but also systematically identifies key sources of RBFE error, including structural fidelity, protein flexibility, ligand pose instability, and disruption of critical binding interactions during alchemical transformations. Furthermore, AlphaFold3 (AF3) was used to model a gp16 structure with higher structural stability than the available cryo-EM structure, and RBFE results indicate that the two models may correspond to distinct functional states (nucleotide-binding preferences) during the substrate translocation cycle.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"8 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283999","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":"Toward a Balanced Description of Ground and Excited States with Transcorrelated F12 Methods.","authors":"Conner Masteran, Bimal Gaudel, Edward F Valeev","doi":"10.1021/acs.jctc.5c01434","DOIUrl":"https://doi.org/10.1021/acs.jctc.5c01434","url":null,"abstract":"<p><p>By correlating only the 1-particle states occupied in the reference determinant, the conventional design for the single-reference R12/F12 explicitly correlated methods biases them toward the ground-state description, thereby making the treatment of response properties of the ground state, and energies and other properties of excited states less robust. While the use of multireference methods and/or extensions of the standard SP-projected geminals can achieve a more balanced description of ground and excited states, here we show that the same goals can be achieved by extending the action of F12 correlators to the occupied and valence unoccupied 1-particle states only. This design choice reflects the strong dependence of the optimal correlation length scale of the F12 ansatz on the orbital energies/structure, and helps to avoid the unphysical raising of the ground-state energy if the F12 geminals are used to correlate pairs of all 1-particle states. The improved F12 geminal design is incorporated into the unitary transcorrelation framework to produce a unitary 2-body Hamiltonian that incorporates the short-range dynamical correlation physics for ground and low-energy excited states in a balanced manner. This explicitly correlated effective Hamiltonian reduces the basis set requirement on the correlation-consistent basis cardinal number by 1 or more over the uncorrelated counterpart for the description of ground-state coupled-cluster singles and doubles (CCSD) energies, vertical excitation energies, and harmonic vibrational frequencies of equation-of-motion CCSD low-energy excited states.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145278446","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 Reliable and Inexpensive Flexible Molecule Crystal Structure Prediction Protocol Based on First Principles.","authors":"Rahul Nikhar,Krzysztof Szalewicz","doi":"10.1021/acs.jctc.5c00628","DOIUrl":"https://doi.org/10.1021/acs.jctc.5c00628","url":null,"abstract":"Crystal structure prediction (CSP) methods are of importance for pharmaceutical, electronic, agricultural, and energetic materials. Most CSPs are performed by minimizing lattice energies of quasi-randomly generated polymorphs using either atom-atom force fields (FFs) or dispersion-augmented periodic density functional theory (pDFT+D) calculations. In the former case, the FFs can be of empirical nature or tailor-fitted to results of ab initio calculations. It has been recently shown that intermonomer FFs fitted to symmetry-adapted perturbation theory interaction energies, inter-aiFFs, perform exceedingly well compared to empirical FFs (empFFs) for crystals with rigid monomers. Here, we show that empFF-based CSPs for crystals with flexible monomers are generally not reliable and design a method for developing intramonomer FFs fitted to ab initio calculations for monomers (intra-aiFFs). These were used together with inter-aiFFs in full-dimensional CSPs to predict the crystal structure of 2-acetamido-4,5-dinitrotoluene with 6 soft degrees of freedom. For the 1000 lowest lattice energy polymorphs predicted by such an aiFF-based approach, pDFT+D calculations were performed without optimizations of geometries. Next, the top-ranked 100 polymorphs were fully optimized using pDFT+D. This protocol resulted in the experimental crystal being ranked as number 2 at much lower costs than those of other reliable approaches. Our method of developing intra-aiFFs should also have important implications for biomolecular simulations.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"88 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145261305","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":"Excited-State Densities from Time-Dependent Density Functional Response Theory.","authors":"Anna Baranova, Neepa T Maitra","doi":"10.1021/acs.jctc.5c00909","DOIUrl":"https://doi.org/10.1021/acs.jctc.5c00909","url":null,"abstract":"<p><p>While the variational principle for excited-state energies leads to a route to obtaining excited-state densities from time-dependent density functional theory, relatively little attention has been paid to the quality of the resulting densities in real space obtained with different exchange-correlation functional approximations or how nonadiabatic approximations developed for energies of states of double-excitation character perform for their densities. Here we derive an expression directly in real space for the excited-state density, which includes the case of nonadiabatic kernels and consequently is able, for the first time, to yield densities of states of double-excitation character. Under some well-defined simplifications, we compare the performance of the local-density approximation and exact-exchange approximation, which are in a sense at the opposite extremes of the fundamental functional approximations, on local and charge-transfer excitations in one-dimensional model systems and show that the dressed Time-Dependent Density Functional Theory (TDDFT) approach gives good densities of double excitations.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273149","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":"Toward Accuracy and Efficiency: A Polarizable Bond-Dipole-Based Water Model.","authors":"Jia-Yi Zhu,Xiao-Nan Jiang,Qiang Hao,Chang-Sheng Wang","doi":"10.1021/acs.jctc.5c00857","DOIUrl":"https://doi.org/10.1021/acs.jctc.5c00857","url":null,"abstract":"A polarizable water model, PBFF-WAT-2025, is developed on the basis of chemical bond dipoles as the fundamental electrostatic sites. In this framework, both permanent and induced dipole contributions are assigned to each bond dipole, providing a physically motivated alternative to atom-centered multipole schemes. For computational efficiency, the induced dipole vectors are constrained to be collinear with the corresponding permanent dipoles. The potential loss of angular flexibility is compensated by the inclusion of orbital-interaction terms, through which the directionality of hydrogen bonding and the essential anisotropy in the electrostatics are incorporated. The accuracy of the model is assessed against CCSD(T) reference data for water clusters, yielding root-mean-square deviations of 1.39 kcal/mol for total interaction energies and 1.10 kcal/mol for three-body contributions. Thermodynamic and dynamic properties of bulk water, including density, enthalpy of vaporization, thermal expansion coefficient, isobaric heat capacity, isothermal compressibility, self-diffusion coefficient, and average dipole moment, are evaluated and shown to be in reasonable agreement with experiment. Although polarization is explicitly treated, computational overhead is minimized by the robustness of the bond-dipole representation, which allows dipole updates to be performed infrequently during molecular dynamics simulations. By balancing physical fidelity with efficiency, the PBFF-WAT-2025 model is demonstrated to provide a transferable and computationally practical framework for long-time scale and large-system simulations of aqueous and biomolecular systems.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"56 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145261093","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":"The Evolving Quest for Chemical Understanding in the Quantum Age.","authors":"Shubin Liu","doi":"10.1021/acs.jctc.5c01299","DOIUrl":"https://doi.org/10.1021/acs.jctc.5c01299","url":null,"abstract":"As quantum mechanics enters its second century, theoretical and computational chemistry stands at a pivotal transition. Traditional orbital-based approaches such as valence bond theory and molecular orbital theory and density-based frameworks like density functional theory have long provided the computational and conceptual foundations for the field. However, the advent of machine learning and quantum computers introduces completely new paradigms for representation, inference, and understanding. In this perspective, we examine how chemical understanding has been evolving in the past century through the lenses of ontology, epistemology, and emergence. We argue that chemical concepts, such as aromaticity, electronegativity, reactivity, and stereoselectivity, are not merely reducible to basic laws of physics but emerge as essential scaffolds linking chemical theories to chemical understanding. We propose a general scheme to obtain chemical understanding from the basic variables of chemical theories. Extending this scheme to deep learning and quantum computing, we suggest roadmaps to harvest chemical understanding from them and then advocate for hierarchical modeling as a new platform that moves beyond the constraints of multiscale modeling. Hierarchical modeling integrates abstraction across scales, captures emergent behaviors, and enables conceptual innovation for hierarchical systems. We conclude that the future of chemical understanding depends less on solving harder physical equations alone and more on epistemological shift characterized by conceptual pluralism, epistemic adaptability, and deeper appreciation of the multilayered ontological structure inherent to molecular systems.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"5 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145247168","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}