Journal of Chemical Theory and Computation最新文献

{"title":"Low-Scaling Equation-of-Motion Coupled Cluster Method for Open-Shell Systems: I. IP-EOM-DLPNO-CCSD","authors":"Marcos Casanova-Páez,Frank Neese","doi":"10.1021/acs.jctc.6c01848","DOIUrl":"https://doi.org/10.1021/acs.jctc.6c01848","url":null,"abstract":"We present the formulation and implementation of an unrestricted/open-shell domain-based local pair natural orbital equation-of-motion coupled-cluster method with single and double excitations for vertical ionization potentials (UHF IP-EOM-DLPNO-CCSD). The method extends the open-shell DLPNO–CCSD reference calculation to the (N – 1)-electron sector by reusing the localized occupied orbitals, pair domains, pair lists, and pair natural orbital spaces generated for the correlated ground state. Removal of an α or β electron is treated in separate spin sectors. The one-hole sector is retained in the fully localized occupied space, whereas the two-hole–one-particle sector is represented in compact, spin-resolved PNO spaces. The accuracy is controlled by the standard LoosePNO, NormalPNO, and TightPNO hierarchy. For ionized states dominated by one-hole character, canonical and local calculations performed with the same quasi-restricted-orbital (QRO) reference give typical RMSD differences of a few hundredths of an eV for the main-group radical and transition-metal benchmark sets. A representative TightPNO comparison for naphthalene further indicates that the additional local IP-EOM approximation contributes less than 0.10 eV for the ten matched states examined. Larger delocalized systems show less regular threshold dependence, and even predominantly one-hole states can exhibit changes greater than 0.1 eV between NormalPNO and TightPNO. Timing calculations for anionic acenes up to heptacene, with 1038 basis functions, show low-order effective scaling for the IP-EOM step. Applications to C–70 and to the Pheophytin radical anion, the latter containing 3020 basis functions, demonstrate that the method can treat large open-shell molecular systems beyond the size range routinely accessible to canonical IP-EOM-CCSD. Finally, comparisons with available experimental data for the N-carbazolyl radical and the ovalene radical cation provide additional context for the calculated vertical ionization energies.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"1 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149368315","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":"Reweighting Free Energy Profiles with Universal Machine Learning Interatomic Potentials for Fast Consensus Building","authors":"Sauradeep Majumdar,Miguel Steiner,Johannes C. B. Dietschreit,Swagata Roy,Daniel Willimetz,Lukáš Grajciar,Rafael Gómez-Bombarelli","doi":"10.1021/acs.jctc.6c02044","DOIUrl":"https://doi.org/10.1021/acs.jctc.6c02044","url":null,"abstract":"Universal machine learning interatomic potentials (MLIPs) have made density functional theory (DFT)-level molecular dynamics highly affordable. However, their rapid proliferation makes it prohibitively expensive to benchmark every new model against the potential of mean force (PMF), the bridge between microscopic atomic fluctuations and macroscopic thermodynamic and kinetic observables. Reweighting the trajectory of a single “source” MLIP onto a suite of target potentials offers a cheaper route, but it is hindered by the statistical collapse of exponential free energy perturbation when the phase-space overlap between potentials is low. We show that for system sizes of practical interest, this collapse is essentially unavoidable, and we quantify it with an information-theoretic diagnostic, the reweighting entropy, that indicates when reweighting can be trusted. To sidestep the collapse, we introduce a systematic, scalable reweighting framework spanning exponential reweighting, the Gaussian approximation, and the energy-only estimator. When applied to the intramolecular radical cyclization of hexenyl (17 atoms), all three estimators perform well and reproduce the target ωB97M-V/def2-TZVP PMF. However, when extended to Li+ transport through a water-solvated zeolite (601 atoms), only the energy-only estimator recovers the PMFs of a diverse suite of MLIPs from a single source simulation by discarding the noisy entropic contribution to the free energy correction. An independent, brute-force umbrella sampling of one of the most divergent targets (MACE-MATPES-r2SCAN) for this system confirms it: beyond the shape of the PMF, both the reaction and activation free energies are recovered within chemical accuracy. The same analysis reveals that the studied MLIPs partition into two clusters, one of plain generalized gradient approximation (GGA) models (PBE, PBE-sol) and one of meta-GGA and/or dispersion-corrected models (PBE-D3, r2SCAN, r2SCAN-D4), reflecting differences in their training data and DFT reference. The resulting protocol thus offers an affordable and reliable route to cross-model consensus on materials properties, even when exact reweighting is statistically intractable.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"14 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149368311","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":"FermiLink: An Agent Harness for Multidomain Scientific Simulations","authors":"Gang Meng,Andres Felipe Bocanegra Vargas,Xinwei Ji,Federico Garcia-Gaitan,Felipe Reyes-Osorio,Jalil Varela-Manjarres,Yafei Ren,Mohammadhasan Dinpajooh,Branislav K. Nikolic,Tao E. Li","doi":"10.1021/acs.jctc.6c01808","DOIUrl":"https://doi.org/10.1021/acs.jctc.6c01808","url":null,"abstract":"Artificial intelligence (AI) agent harnesses have been developed for autonomous scientific simulations, but most current agent harnesses are tested on a single or a small set of software packages. Herein, FermiLink, an extensible open-source agent harness, is introduced for multidomain scientific simulations. Its key design principle is the separation of package knowledge bases from simulation workflows, so that simulation workflows in FermiLink, from figure-level simulations to full-paper-level research on high-performance computing clusters, operate uniformly among supported packages via a four-layer progressive disclosure mechanism. This agent harness is specifically optimized for high-performance computing (HPC) clusters, enabling multiday, multistep scientific simulations in the absence of human intervention. Using OpenAI Codex as the agent provider, the capabilities of FermiLink are demonstrated across approximately 50 scientific software packages spanning nine research domains from chemistry to engineering. Systematic benchmarks on 132 real-world figure-level reproduction tasks with 44 packages show that FermiLink reproduces 74 (56.1%) of published figures with simulations, among which 30 (22.7%) achieve high-fidelity agreement and 35 reach qualitative agreement with the target figures. A smaller set of human expert-guided reproduction benchmarks with 10 packages in physics and chemistry further highlights the importance of expert insights for improving the simulation fidelity. Beyond reproduction, a single-blinded study demonstrates that FermiLink can produce research-grade results on unpublished polariton physics problems when provided with sufficiently detailed research objectives. Overall, FermiLink provides a scalable research infrastructure that may accelerate the path from scientific questions to computational results across diverse domains.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"4 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149368313","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":"Sequence Model-Based Prediction and QM/MM Assessment of CYP2C19 Variant Effects on Mephenytoin Oxidation","authors":"Peter A. Ramdhan,Gustavo Seabra,Wen Jun Xie,Larisa H. Cavallari,Chenglong Li","doi":"10.1021/acs.jctc.6c01085","DOIUrl":"https://doi.org/10.1021/acs.jctc.6c01085","url":null,"abstract":"Cytochrome P450 2C19 (CYP2C19) genetic variation contributes to interindividual differences in drug metabolism, yet relating sequence-level variation to substrate-specific catalytic mechanisms remains challenging. Here, we combine a generative sequence model based on the maximum entropy (MaxEnt) framework for mutation scoring, published biochemical activity data, molecular dynamics (MD) simulations, and quantum mechanics/molecular mechanics adaptive steered molecular dynamics (QM/MM ASMD) calculations to examine CYP2C19 variant effects on S-mephenytoin oxidation. In the primary correlation analysis, MaxEnt scores showed nonsignificant negative rank trends with Vmax and CLint, whereas Km showed no corresponding rank association. CYP2C19*1A (WT) was used as the reference system, and CYP2C19*23 and CYP2C19*26 were selected as contrasting variants for atomistic analysis. MD simulations revealed variant-dependent changes in conformational sampling, correlated motions, and substrate positioning, but the population of geometries satisfying a predefined reactive distance-angle criterion did not reproduce the experimental activity trend. At the production pulling rate, the Seed 1 QM/MM-ASMD profiles showed a lower C12 oxygen-addition barrier for CYP2C19*23 and a higher barrier for CYP2C19*26 relative to CYP2C19*1A. Additional CYP2C19*1A and CYP2C19*23 starting configurations yielded a lower three-seed mean barrier for CYP2C19*23 at that pulling rate, although the barrier ranges overlapped and starting-configuration dependence was appreciable, and a slower-pulling control showed substantial rate sensitivity. The sampled NIH-shift profiles exhibited apparent low barriers in all three systems; however, substantial discrepancies between partition-level nonequilibrium-work estimators precluded establishing quantitatively converged CV2 barrier magnitudes. Thus, the calculations support qualitative differences among the sampled reaction profiles but do not quantitatively reproduce the magnitude of the experimental kinetic differences. The combined sequence, MD, and QM/MM workflow provides a framework for prioritizing variants and developing substrate-specific mechanistic hypotheses while making the sampling limitations explicit.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"24 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149368310","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":"Consistency, Cancellation, and Experiment in Quasi-Harmonic Thermochemistry","authors":"Haide Wu,Roope Halonen","doi":"10.1021/acs.jctc.6c01634","DOIUrl":"https://doi.org/10.1021/acs.jctc.6c01634","url":null,"abstract":"For weakly bound molecular complexes, the Gibbs energy is often limited less by the electronic interaction energy, now computed to near chemical accuracy, than by the statistical-mechanical treatment of their low-frequency intermolecular vibrations. The standard remedy, Grimme’s quasi-harmonic correction, rescales the entropy of these modes toward a free-rotor limit while leaving their energy harmonic; because both derive from the same partition function, this is thermodynamically inconsistent. Applied consistently to energy and entropy, the correction largely cancels over the dominant intermolecular modes, whereas the entropy-only form leaves a one-sided shift that grows with system size. We test this against experiments: carboxylic acid dimerization, methanol vapor association, and sulfuric acid–ammonia nucleation in the CLOUD chamber. The entropy-only correction departs from experiment in all three cases, while the plain harmonic treatment matches the dimerization data and, supplemented by a physically grounded anharmonic term, the measured alcohol vapor properties and nucleation barriers. For such complexes, thermodynamic consistency is a prerequisite that no empirical entropy correction can replace.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"9 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149368317","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":"Alchemical Transfer Free Energy Perturbation Simulations Reveal Entropic Mechanism Governing the Binding of a Charged Peptide to a Protein Target","authors":"Xavier E. Laracuente,Bryan M. Delfing,Xingyu Luo,Audrey Olson,William Jeffries,Steven R. Bowers,Kenneth W. Foreman,Kyung Hyeon Lee,Mikell Paige,Kylene Kehn-Hall,Christopher Lockhart,Dmitri K. Klimov","doi":"10.1021/acs.jctc.6c01598","DOIUrl":"https://doi.org/10.1021/acs.jctc.6c01598","url":null,"abstract":"We combined alchemical transfer free energy perturbation (FEP) and replica exchange with solute tempering (REST) molecular dynamics to probe the energetics of the binding of a charged peptide to a protein target. For this purpose, we have selected the coreNLS peptide KKPKKE, the conserved fragment from the nuclear localization signal (NLS) sequence in viral capsid protein binding to nuclear transporter importin-α (impα). This peptide binds to impα, natively forming a specific pose similar to that resolved experimentally. The two main outcomes of our work are as follows. First, we further develop the FEP methodology. Alchemical transfer is a rarely used version of FEP, in which an unbound peptide is gradually decoupled, while the bound peptide is coupled. Because the net charge of the system remains unchanged, no charge-related corrections within FEP are necessary. Additionally, our FEP protocol utilizes a “laissez faire” soft-walled flat-bottom spherical restraint, which does not affect a ligand as long as it occupies the major NLS binding site in impα. We showed that combining FEP with REST molecular dynamics affords exhaustive sampling of the binding process and reduces the free energy error down to 0.4 kcal/mol. Second, we found that the coreNLS binds impα with moderate affinity of ΔG0b = −4.6 kcal/mol. We analyzed the factors contributing to binding energetics. Direct interactions between the peptide and impα favor binding and are likely to be responsible for largely native binding pose of the coreNLS. These direct binding interactions are supplemented by the gains in water–water, ion–ion, and water–ion interactions. Both, direct and indirect, enthalpic gains are about equally important, but cannot compete with severe enthalpic losses stemming from the expulsion of water and ions from the binding interface. As a result, the net binding enthalpy is unfavorable. The factor, which ultimately “saves” coreNLS binding to impα, is a strong entropic gain occurring upon water and ion release from the binding interface. Based on our investigation, we classify the mechanism governing coreNLS binding to impα as entropic. Our isothermal titration calorimetry measurements confirm the estimates of ΔG0b provided by FEP. By connecting with our prior studies and other reports, we propose that such binding mechanism may be applicable to other charged peptides reflecting complex interplay between binding enthalpy and entropy. Interestingly, our data suggest that the ligands binding diffusively or by adopting specific poses may utilize an entropic binding mechanism.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"11 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149360507","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 Computational Framework for the Determination of the Binding Affinity of Peripheral Proteins to Homogeneous Membranes","authors":"Stephen Gee,Erin J. Adams,Christophe Chipot,Ka Yee C. Lee,Benoît Roux","doi":"10.1021/acs.jctc.6c00889","DOIUrl":"https://doi.org/10.1021/acs.jctc.6c00889","url":null,"abstract":"Peripheral membrane-binding proteins (PMPs) are essential to immunological and neurological processes, and disruptions in their membrane interactions are implicated in cancer, neurodegeneration, and autoimmune diseases. Their functional diversity arises from the wide range of mechanisms by which they associate with lipid surfaces, motivating atomistic computational frameworks capable of quantifying binding energetics. We present such a methodology and demonstrate it using Bacillus thuringiensis phosphatidylinositol-specific phospholipase C (BtPI–PLC), a 296-residue virulence factor that preferentially associates with phosphatidylcholine (PC) membranes. Experimental studies report dissociation constants near 24 μM for wild-type BtPI–PLC binding to PC vesicles, corresponding to a standard free energy of −6.6 kcal/mol. BtPI–PLC associates with membranes through cation−π interactions involving Y88 and Y246, hydrophobic contacts from helix B, and other noncovalent interactions, making comprehensive sampling challenging. Here, we present a statistical mechanical geometrical route formulation based on the potential of mean force for the quantitative characterization of dilute PMP binding to homogeneous membranes. Using enhanced sampling via well-tempered metadynamics and extended adaptive biasing force, we obtain a computational estimate of the standard binding free energy, −6.2 ± 0.3 kcal/mol, consistent with experimental estimates for BtPI–PLC membrane association.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"6 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149360553","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":"Exploring Chemical Concepts and Reactivity from Conceptual Density Functional Theory in Excited States via the ΔSCF Approach","authors":"Bin Wang,Paul Geerlings,Frank De Proft","doi":"10.1021/acs.jctc.6c01493","DOIUrl":"https://doi.org/10.1021/acs.jctc.6c01493","url":null,"abstract":"Along with the recent development of the ΔSCF approach for excited state electronic structure description using density functional theory (DFT), we extend and develop conceptual density functional theory (CDFT) for evaluating chemical concepts and reactivity descriptors for both ground and excited states. Thereby, the fundamental energy functional EJ[{npσ},v(r)] based on the generalized adiabatic connection Kohn–Sham (GAC-KS) theorem is introduced. Offering a straightforward interpretation of the reactivity of excited states analogous to that of the ground state. In this framework, ground state CDFT naturally emerges as a special case when the derivative with respect to the number of electrons is taken at the frontier orbital occupation, i.e., dN = dnf. Starting from the ground state system, the spin-polarized analytical linear response function (LRF) is tested to examine the atomic shell structure for alkali atoms as well as the reactive region upon electron addition and removal processes using the Fukui kernel. The behavior of the LRF is then illustrated for ground, singly excited, and doubly excited states of a set of molecular systems, revealing the expected trends and nature of bond polarizability and bonding character. The analytical Fukui function is also presented here for its ability to describe local electrophilicity and nucleophilicity for ground and excited states. An inverse relationship for the condensed electrophilic and nucleophilic Fukui functions is observed between the ground and excited states for a set of small molecules, including substituted benzenes. The dual descriptor obtained from the analytical Fukui function via a finite difference approximation is applied to interpret the Woodward–Hoffmann (WH) rules for pericyclic reactions. For both thermally driven and photoinduced ring cyclization processes at the ground and excited states, respectively, the dual descriptor successfully translates the WH rules from molecular orbital context into a purely density-based language.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"6 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149360538","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":"Nucleophilicity from a Conceptual DFT Viewpoint: A Four-State Ensemble-Inspired Model","authors":"Paulino Zeron,Anaid Flores,José L. Gázquez,Marco Franco-Pérez","doi":"10.1021/acs.jctc.6c01595","DOIUrl":"https://doi.org/10.1021/acs.jctc.6c01595","url":null,"abstract":"By taking advantage of the fundamental convexity of the exact energy as a function of the number of electrons, we extrapolate the straight-line segments connecting the N and N + 1 states and N – 2 and N – 1 states in a four-state ensemble-inspired model. These segments intersect at a unique point that determines a fractional charge transfer condition, ΔNint−=−λ ⁠, which naturally contemplates the reactivity of the cation and neutral forms in terms of their hardness. The energy evaluated at the intersection point, Ni, and the energy evaluated at −λ in the ensemble segment, Nl ⁠, give rise to our proposed descriptors that contribute to the electronic panorama of the donation process and describe the reactivity of a set of molecules in specific conditions. The performance of the indicators as nucleophilic indices was evaluated in five chemical reactions: the oxidation of metals, the proton affinity of amines, the stability of coordinated metals that follow the Irving–Williams series, and the kinetic substitution of indoles and alkenes. The nucleophilicity indices proposed are an important complement to the electrophilicity index because they are based on a different response that, although they may lead to similar results with respect to the correlation with a given property, they may be used to recognize dominant aspects of the electronic structure in a chemical interaction. The results obtained support their use as complementary descriptors of the intrinsic electronic contribution to nucleophilic reactivity within specified reaction families.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"9 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149360522","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":"Intra- and Intermolecular Interactions in Cellobiose: Benchmarking Accelerated Computational Methods for Cellulose","authors":"Felicia Andersson,Shokirbek Shermukhamedov,Valentina Basoli,Fabiana Arduini,Kersti Hermansson,Peter Broqvist","doi":"10.1021/acs.jctc.6c01354","DOIUrl":"https://doi.org/10.1021/acs.jctc.6c01354","url":null,"abstract":"Access to accelerated computational methods at the electronic and atomistic scales is important in materials modeling, as it will allow more realistic system descriptions. Against this background, a systematic study of a range of electronic/atomistic methods applied to cellobiose monomers and dimers is presented, with the aim of identifying methods that achieve a significant acceleration of cellulose computations compared to hybrid DFT methods while retaining adequate accuracy. We benchmark such methods, namely the semiempirical quantum-mechanical tight-binding GFNn-xTB (n = 1,2) and G-xTB methods, the MACE-OMol-0 machine-learning potential, and the CHARMM36 force field, against three DFT references (ωB97M-V, B3LYP-D3, PBE-D3) for gas-phase cellobiose monomers and dimers, focusing on structures, energies, and vibrational properties. Cellobiose monomers and dimers, as presented in this work, do not represent the structural complexity of cellulose, but they provide tractable structural models for assessing the qualities of the selected computational models regarding cellobiose–cellobiose intermolecular interactions that are also present in cellulose. We find that (i) the chain–chain and sheet–sheet dimer interactions are of comparable magnitude, suggesting that both intermolecular dispersion and hydrogen bonding make important contributions to dimer stability, so accurate treatment of noncovalent interactions the calculations is essential; (ii) GFN2-xTB and G-xTB reproduce most conformations well, with a speed-up of two to three orders-of magnitude compared to the DFT calculations, but fail for puckered, strained conformations, artificially improving apparent dimer-energy agreement with DFT; (iii) MACE reaches near-DFT accuracy with a further order of magnitude speed-up, although in a few cases fails to reproduce the hybrid DFT conformations. This is especially true for the chain–chain dimer structure, which is also reflected in a significant deviation of the chain–chain energy-distance potential curve, which highlights the importance of system-dependent model validation (as was done here) and suggests a need for model fine-tuning for cellulose systems; (iv) CHARMM36 has some conformational and energetic limitations,but being 30,000× faster than G-xTB (itself orders of magnitude faster than DFT), remains practical for qualitative studies.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"26 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149360552","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}