Journal of Chemical Theory and Computation最新文献

{"title":"Modeling the Impact of Active Site Mutations on the Quenching Fate and Cyclization Depth of a Rare Oxidosqualene Cyclase","authors":"Chenxu Liu,&nbsp;Shun Liang,&nbsp;Ying Zheng,&nbsp;Feng Wang,&nbsp;Jiaqi Jiao,&nbsp;Bing Li,&nbsp;JinCai Liang,&nbsp;Zhongqiu Liu,&nbsp;Lixin Duan,&nbsp;Ruibo Wu,&nbsp;Fan Zhang","doi":"10.1021/acs.jctc.6c01306","DOIUrl":"10.1021/acs.jctc.6c01306","url":null,"abstract":"<p>Oxidosqualenecyclases (OSCs) convert linear 2,3-oxidosqualeneinto diverse polycyclic triterpenoids. The precise control over highlyreactive carbocation intermediates, particularly the ultimate quenchingmechanism (deprotonation vs hydroxylation), remains a fundamentalchallenge in mechanism-driven enzyme reshaping. Here, we investigateAaOSC-20433, a rare OSC from <em>Artemisia argyi</em> exhibitingabsolute specificity for pure deprotonation to produce dammara-20,24-dien-3β-ol.This starkly contrasts with the homologous dammarenediol synthasefrom <em>Panax ginseng</em> (PgDDS), which favors hydroxylationto yield dammarenediol II. Integrating multiscale QM/MM simulationsand site-directed mutagenesis, we modeled the impact of crucial activesite mutations on the reaction cascade. Our simulations revealed thatS411 acts as a general base governing the terminal deprotonation.More importantly, we demonstrate that mechanism-guided active sitesubstitutions can dramatically alter the chemical trajectory. Relaxingsteric constraints (F728A) induces catalytic promiscuity to yieldtricyclic and tetracyclic products. Furthermore, the L259Y mutationsignificantly alters the quenching network. It unlocks the hydroxylationpathway to form dammarenediol II and acts as an engineered base extendingcyclization depth to yield the pentacyclic lupeol. Notably, combiningthese functional loci (L259Y+F728S) reveals notable synergistic epistasisbetween the steric cavity and the proton-transfer network, drivingcompetitive hydration events to diversify the hydroxylated productprofile. This study provides a comprehensive mechanistic frameworkfor understanding how OSC active site mutations govern product specificity,offering a robust theoretical basis for the tailored, mechanism-drivenfunctional reprogramming of triterpene synthases in synthetic biology.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"22 19","pages":"10465–10474"},"PeriodicalIF":5.8,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149003364","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":"Bayesian Learning of Distance Metrics Beyond RMSD for Biomolecule Alignment, Clustering, and Domain Identification","authors":"Saumyak Mukherjee,&nbsp;Gerhard Hummer","doi":"10.1021/acs.jctc.6c01395","DOIUrl":"10.1021/acs.jctc.6c01395","url":null,"abstract":"<p>Root-mean-square deviation (RMSD) is the standard metricof structuralcomparison in molecular dynamics (MD) simulations. In its conventionalform, RMSD assigns equal weight to all atoms regardless of mobility.Hence, flexible loops and disordered regions can dominate a globalRMSD, while the rigid functional core contributes negligibly to theoverall metric. To address this issue, we introduce the Bayes-optimalRMSD (<em>BRMSD</em>), which optimizes per-atom weights jointlywith structural averages by maximizing a Bayesian posterior. In atrade-off between low RMSD and weight uniformity, a position-fluctuationparameter σ controls the transition from classical RMSD (σ→ ∞) to a progressive focus on a rigid core (σ→ 0). The BRMSD framework supports analysis modules for structuralalignment, focused alignment onto a user-specified domain, trajectorysmoothing, soft <em>K</em>-means conformational clustering,and rigid-domain identification. These modules are implemented inthe open-source Python package <span>BRMSD</span> and benchmarkedon two MD systems, the endoplasmic reticulum translocon-associatedprotein SND3 and the phosphotransferase adenylate kinase.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"22 19","pages":"10475–10487"},"PeriodicalIF":5.8,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149091976","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":"Locally Updated Bootstrap Embedding","authors":"Minsik Cho,&nbsp;Troy Van Voorhis","doi":"10.1021/acs.jctc.6c00809","DOIUrl":"10.1021/acs.jctc.6c00809","url":null,"abstract":"<p>Bootstrap Embedding (BE) has recentlydemonstrated animpressiveability to produce highly accurate single-point energies at a lowcomputational cost, utilizing systematically determined fragmentsthat overlap with each other. In many chemical applications, suchas scanning the potential energy surface, one performs numerous single-pointcalculations that differ by local geometric changes. This often leadsto a frustratingly time-consuming process, even with computationallyaffordable methods like BE. We present here a locally updated versionof BE that dramatically accelerates these types of calculations witha minimal loss in accuracy. Specifically, we propose a method thatupdates only the fragments that involve the change in geometry, whilereusing information from a single correlated calculation at a referencegeometry for all other fragments. We illustrate the key characteristicsof this method and compare it with conventional BE. This novel schemecan potentially lead to a correlation method that scales sub-linearlyin time with respect to system size. It exhibits chemical accuracy(&lt;1 kcal/mol energy error) for bond stretches of about 1 Åor rotations of tens of degrees relative to the reference geometry,while recomputing only a small number of fragments, independent ofsystem size. We discuss potential applications in simulating realisticchemical phenomena, such as scanning the potential energy surface,reaction pathway studies, molecular dynamics simulations, and geometryoptimizations.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"22 19","pages":"10012–10021"},"PeriodicalIF":5.8,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148973848","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":"Overcoming Sampling Limitations Using Machine-Learned Interatomic Potentials: The Case of Water-in-Salt Electrolytes","authors":"Luca Brugnoli,&nbsp;Mathieu Salanne,&nbsp;A. Marco Saitta,&nbsp;Alessandra Serva,&nbsp;Arthur France-Lanord","doi":"10.1021/acs.jctc.6c00579","DOIUrl":"10.1021/acs.jctc.6c00579","url":null,"abstract":"<p>Machine-learned interatomicpotentials hold the promise to enablethe modeling of highly concentrated liquids over meaningful time scales,far from reach for current <em>ab initio</em> electronic structuremethods. Here we evaluate the performances of various MACE potentialsin modeling a 21 m water-in-salt electrolyte based on lithium bis(trifluoromethanesulfonyl)imide.We test out-of-the-box foundation models, as well as both fine-tuningand from-scratch training strategies. Our simulations demonstratethat surrogate models allow us to overcome sampling limitations of <em>ab initio</em> molecular dynamics, reaching an excellent agreementwith experimental observables such as the structure factor. We alsodemonstrate the benefit of fine-tuning a foundation model over trainingfrom scratch, in terms of data efficiency, but most importantly asa means to provide information regarding configurations hard to sample,such as short Li⁺–Li⁺ distances. Finally,we show that depending on the reference exchange-correlation functional,empirical dispersion correction schemes can be detrimental. All inall, our work shows that machine-learned interatomic potentials area good fit for the modeling of highly concentrated electrolytes overlong time scales.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"22 19","pages":"9927–9939"},"PeriodicalIF":5.8,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149010355","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":"An Open Implementation of MSEVB for Reactive Force Field Simulation with Simple Energy-Based Coupling","authors":"Blake I. Armstrong,&nbsp;Peter R. Spackman,&nbsp;Luc M. LeBlanc,&nbsp;Paolo Raiteri,&nbsp;Julian D. Gale","doi":"10.1021/acs.jctc.6c01182","DOIUrl":"10.1021/acs.jctc.6c01182","url":null,"abstract":"<p>Chemical reactivitymodeling in large systems over extendedtimescales is computationally and theoretically challenging; <em>ab initio</em> methods are too expensive, while classical force fieldscannot handle bond breaking/formation. Existing solutions like reactiveforce fields require extensive expertise to develop, and machine-learnedapproaches often need prohibitively large, high-quality data setsfor training. These barriers have hindered the modeling of reactivechemical processes. Multistate empirical valence bond (MSEVB) theoryoffers an alternative by enabling conventional unreactive force fieldsto be mixed in a controlled manner to selectively describe chemicalreactions. However, existing MSEVB implementations are often field-specific,have license-restricted distribution, or rely on complex parametrizationschemes. This work presents a new open-source, general MSEVB implementation,designed to make reactive modeling more accessible to nonexperts.Specifically, the implementation here focused on simple energy-basedcoupling, thereby eliminating the need for complex geometry-basedcoupling approaches, significantly lowering the barrier to entry forreactive force field development. This generalized approach is demonstratedto reproduce proton transfer behavior in Y-doped and undoped BaZrO₃, bulk water and liquid imidazole, as well as other formsof reactivity, such as electron migration in LiCoO₂. Wedemonstrate that only two fitted parameters are needed to accuratelymodel symmetric transfer across the three chemically diverse proton-conductingsystems studied.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"22 19","pages":"10263–10280"},"PeriodicalIF":5.8,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149049665","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":"Mechanical Tuning of Singlet–Triplet Resonance for Efficient Triplet–Triplet Annihilation Upconversion","authors":"Edgard Miranda-Sáenz,&nbsp;Pedro B. Coto,&nbsp;Luis Manuel Frutos","doi":"10.1021/acs.jctc.6c01488","DOIUrl":"10.1021/acs.jctc.6c01488","url":null,"abstract":"<p>Triplet–triplet annihilation upconversion dependson a near-resonantenergetic balance between the relevant singlet and triplet excitedstates. Here we introduce a computational framework for mechanicallytuning this balance by applying an external force that permits tolocate the molecular geometry reaching the singlet–tripletresonance condition, i.e., <em>E</em>_{<em>S</em>₁} – <em>E</em>_{<em>S</em>₀} = 2(<em>E</em>_{<em>T</em>₁} – <em>E</em>_{<em>S</em>₀}). Our approach formulates this problem as a constrainedoptimization in which the force magnitude is minimized while enforcingthe target energetic resonance condition. Using a local quadraticmodel for the triplet-state potential energy surface together witha linearized description of the relevant energy gaps, we derive aminimum-force update procedure to obtain the optimal displacementand the associated external force. The resulting algorithm providesthe mechanically controlled geometry and the optimal force vectorrequired to reach it. The method offers a practical computationalroute to identify mechanically accessible structures with improvedupconversion characteristics, paving the way for the design of mechanoresponsivechromophores and materials with stress-tunable optical behavior.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"22 19","pages":"10381–10390"},"PeriodicalIF":5.8,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149049667","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":"How Accurately Can We Describe Spin Crossover?","authors":"Angel Albavera-Mata,&nbsp;Daniel Mejía-Rodríguez,&nbsp;Niranjan Govind,&nbsp;Ajay Panyala,&nbsp;Richard G. Hennig,&nbsp;S. B. Trickey","doi":"10.1021/acs.jctc.6c01104","DOIUrl":"10.1021/acs.jctc.6c01104","url":null,"abstract":"<p>The complicated physicochemical properties of metal complexesthatexhibit thermal spin crossover make it difficult for routine electronicstructure calculations to yield an accurate transition temperatureprediction, <em>T</em>_1/2. The difficulty liesin the intricate connection between the spin-crossover energy, whichis a molecular spectroscopic property, and <em>T</em>_1/2, a condensed-phase property. Here we show how to obtainspin-crossover energies systematically by reverse engineering of experimental <em>T</em>_1/2 data. The protocol is based upon fittingthe range separation parameter, ω, in the hybrid LC-ωPBEdensity functional to reproduce the experimental <em>T</em>_1/2 values for a series of metal complexes. We provideinsights into the sources of variations of at least ±15 kJ mol^–1 found from common exchange and correlation functionalsby comparing their performance against our reference data. By analysisof the sensitivity of transition temperatures to ±1% shifts inthe range separation parameter, we determined a typical uncertaintyof ±50 K for them, and a ±2 kJ mol^–1 uncertaintyin the extracted spin-crossover energies due to ±1% variationsof <em>T</em>_1/2. Lastly, we present results fromthe high-level, all-electron coupled cluster method for eight of thesmaller molecules in the reference data set, and discuss the influenceof the truncation of the excitation series upon the spin state energies.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"22 19","pages":"10064–10077"},"PeriodicalIF":5.8,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149090834","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":"Analytical and Separable Representation of Coulomb-like Potentials","authors":"Subhra K. Das,&nbsp;Annika Bande,&nbsp;Daniel Peláez","doi":"10.1021/acs.jctc.6c00636","DOIUrl":"10.1021/acs.jctc.6c00636","url":null,"abstract":"<p>In this article, low-rank separable analytical representationsof Coulomb-like potentials are presented. Cartesian coordinates areemployed for the sake of generality. The original potential is regularizedto avoid the numerical divergence associated with the coalescenceregion. Furthermore, a range-separation approach is adopted. The long-rangepart, being smooth and well-behaved, can be directly expressed inour functional sparse Tucker Finite Basis Representation (sparse TuckerFBR). On the other hand, the short-range part, which contains thetamed singularity, is expressed using a sparse spectral representation.The quality and accuracy of the full sparse Tucker expression is demonstratedby comparison to the two-interacting-electron-in-a-box model.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"22 19","pages":"10001–10011"},"PeriodicalIF":5.8,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149090892","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":"Covariant Local Matrix Density Approximation through Spectral Reconstruction in Multistate Density Functional Theory","authors":"Alexander Humeniuk,&nbsp;Yangyi Lu,&nbsp;Jiali Gao","doi":"10.1021/acs.jctc.6c01081","DOIUrl":"10.1021/acs.jctc.6c01081","url":null,"abstract":"<p>A covariant local matrix density approximation (LMDA)is introducedwithin multistate density functional theory based on subspace invarianceand the spectral decomposition of the matrix containing state andtransition densities. The exchange-correlation matrix functional isconstructed through spectral reconstruction of this matrix density,whereby local exchange-correlation functionals are incorporated asspectral-channel functionals within a covariant matrix-functionalformalism. The resulting formulation preserves exact normalizationof the exchange-correlation matrix hole, recovers ground-state densityfunctional theory in the single-state limit, and preserves spin-multipletdegeneracy through covariance of the spin matrix functional underspin rotations. Combined with multistate self-consistent-field (MSSCF)optimization, the present framework enables fully variational calculationsof interacting ground and excited states. Applications to atomic excitations,H₂ dissociation, ethylene torsion, and cyclobutadiene automerizationreveal that the resulting MSDFT/LMDA approach captures essential multistateand strong-correlation physics, including static correlation and spinsymmetry. The key insight is that the central obstacle in extendingdensity functional theory to coupled electronic states is not necessarilythe lack of appropriate scalar exchange-correlation approximations,but the lack of a covariant matrix-functional formalism in which suchfunctionals can operate. The present MSDFT/LMDA provides a directrealization of this matrix-functional formalism.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"22 19","pages":"10324–10340"},"PeriodicalIF":5.8,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149049668","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":"Predicting the Radical Character of Open-Shell Nanographenes with the GVB-Based Block-Correlated Coupled Cluster Theory","authors":"Xiaochuan Ren,&nbsp;Jingxiang Zou,&nbsp;Jun Lin,&nbsp;Cong Sun,&nbsp;Wei Li,&nbsp;Shuhua Li","doi":"10.1021/acs.jctc.6c01707","DOIUrl":"10.1021/acs.jctc.6c01707","url":null,"abstract":"<p>Open-shell nanographenes (NGs) possessunique electronicpropertiesthat hold promise for next-generation carbon-based materials, yettheir rational design is hampered by the lack of quantitative toolsto predict their radical character. Empirical rules such as Clar’saromatic sextet rule and the Fries rule provide useful qualitativeguides for closed-shell systems but inherently fail for open-shellNGs, where the ground state is better described as a resonance hybridof closed-shell and open-shell structures. Here, we present a furtherdevelopment of the generalized valence-bond-based block-correlatedcoupled cluster (GVB-BCCC) theory and demonstrate its applicationin qualitative and quantitative predictions of the radical characterin open-shell NGs. Four methodological advances are reported: (1)a systematic search procedure of multiple GVB solutions that enablesthe computational identification of distinct resonance structures(closed-shell, diradical, and tetraradical forms) through tailoredinitial orbital guesses; (2) the first implementation of GVB-BCCC4for triplet ground states, extending the framework to systems withtriplet ground states; (3) the first implementation of the unrelaxedone-particle density matrix for singlet GVB-BCCC4, enabling the extractionof natural orbital occupation numbers (NOONs) as a rigorous, quantitativemeasure of radical character directly from the GVB-BCCC4 wavefunction;and (4) the introduction of a relative local correlation energy (RLCE)index for evaluating local aromaticity in individual benzene-likerings. By exploiting the fact that distinct GVB solutions map to chemicallyintuitive resonance forms, our approach is able to identify the dominantresonance structure through accurate GVB-BCCC4 calculations on topof the respective GVB references. Critically, by comparing the uncorrelatedGVB solutions with the fully correlated GVB-BCCC4 results, we canunambiguously determine whether the radical character of a given systemoriginates from the π-skeleton topology (a resonance-driveneffect) or from interpair electron correlation─a distinctionthat remains inaccessible to empirical rules or conventional methods.Our approach is then applied to 11 representative NGs, including systemswith up to 66 π orbitals. The radical character indices fromGVB-BCCC4 show excellent agreement with DMRG-CASCI reference data,while broken-symmetry DFT is found to be unreliable for systems withpronounced polyradical character. The singlet–triplet energygaps calculated at the GVB-BCCC4 level also agree well with availableexperimental values. This work establishes GVB-BCCC as a predictivetool for understanding the structure–property relationshipsof open-shell systems and for guiding the rational design of carbon-basedfunctional materials.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"22 19","pages":"10213–10226"},"PeriodicalIF":5.8,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149091932","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}