Journal of Chemical Theory and Computation最新文献

{"title":"Approaching Coupled Cluster Accuracy with Positive Semidefinite Vertex Corrected Self-Energies","authors":"Yaroslav Pavlyukh,Fabien Bruneval,Arno Förster","doi":"10.1021/acs.jctc.6c01644","DOIUrl":"https://doi.org/10.1021/acs.jctc.6c01644","url":null,"abstract":"Hedin’s formalism of functional derivatives is a successful method for systematically constructing correlated electronic theories, largely due to the success of its lowest-order self-energy expansion, the GW approximation. Beyond GW, diagrammatic resummation schemes attempt to mix correlations simultaneously across all particle-particle and particle-hole channels. Because such a comprehensive treatment is computationally prohibitive for realistic molecular systems, a highly effective alternative is to fully account for electronic correlations in one specific channel, typically the particle-hole channel. This idea was recently implemented for molecular systems, yielding a self-energy expressed in terms of excited-state energies and transition amplitudes from the solution of the Bethe–Salpeter equation, rather than the random-phase approximation used in GW. While this approach is predictive and numerically efficient, it violates the fundamental positive-definiteness constraint on the electron spectral function in certain energy ranges. In this study, we resolve this physical flaw by deriving a positive-semidefinite (PSD) extension of the theory using a rigorous framework based on the nonequilibrium Green’s function formalism. The PSD constraint introduces new scattering channels and triplet intermediate states and restores the correct physical behavior. We demonstrate that it consistently improves quasiparticle energies across standard molecular benchmarks, with an accuracy comparable to coupled-cluster reference calculations.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"32 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149374730","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":"Equivariant Interatomic Potentials without Tensor Products","authors":"Thiago Reschützegger,Sarp Aykent,Gabriel Jacob Perin,Bruno Henrique Nunes,Flaviu Cipcigan,Rodrigo Neumann Barros Ferreira,Mathias Steiner,Fabian L. Thiemann","doi":"10.1021/acs.jctc.6c00712","DOIUrl":"https://doi.org/10.1021/acs.jctc.6c00712","url":null,"abstract":"Foundational machine-learned interatomic potentials have emerged as powerful tools for atomistic simulations, promising near first-principles accuracy across diverse chemical spaces at a fraction of the cost of quantum-mechanical calculations. However, the most accurate equivariant architectures rely on Clebsch–Gordan tensor products whose computational cost scales steeply with angular resolution, creating a trade-off between model expressiveness and inference speed that ultimately limits practical applications. Here we introduce Geodite, an equivariant message-passing architecture that replaces tensor products while incorporating physical priors to ensure smooth, well-behaved potential energy surfaces. Trained on the Materials Project trajectories dataset of inorganic crystals, Geodite-MP achieves accuracy competitive with leading methods on benchmarks for materials stability prediction, thermal conductivity, phonon-derived properties, and nanosecond-scale molecular dynamics, while running 3–5× faster than models performing similarly. By combining predictive accuracy, computational efficiency, and physicality, Geodite enables faster large-scale atomistic simulations and high-throughput screening that would otherwise be computationally prohibitive.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"506 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149374731","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":"Can Phaseless Auxiliary-Field Quantum Monte Carlo with Broken Symmetry Trials Describe Iron–Sulfur Clusters?","authors":"Eirik F. Kjønstad,Huanchen Zhai,James Shee,Sandeep Sharma,Garnet Kin-Lic Chan","doi":"10.1021/acs.jctc.6c01749","DOIUrl":"https://doi.org/10.1021/acs.jctc.6c01749","url":null,"abstract":"Phaseless auxiliary-field quantum Monte Carlo (AFQMC) has in several cases been found to perform well on strongly correlated systems, including compounds containing transition-metal elements. Here, we benchmark the method for three iron–sulfur clusters ([2Fe-2S], [4Fe-4S], and the FeMo cofactor) using a hierarchy of systematically improved trial states derived from coupled cluster (CC) theory, including up to quadruple excitations relative to the Hartree–Fock (HF) reference, as well as multi-Slater trial states derived from unrestricted density matrix renormalization group wave functions. Our results reveal for these systems that, as the symmetry-broken trial is improved beyond the mean-field level, the phaseless AFQMC energy can become less accurate, and in some cases even less accurate than the underlying trial projected energy itself, displaying an inverted energy pattern that is only corrected once the trial fidelity is sufficiently high. For [2Fe-2S], we show that a decreased accuracy in the AFQMC energy can coincide with a simultaneous improvement in the trial state and the walker ensemble, as measured by their fidelity relative to the exact ground state, a behavior which is allowed by the nonvariational nature of the phaseless AFQMC energy estimator. We further find that this is not solely due to the use of spin-unrestricted trial states, as the inversion persists in [2Fe-2S] when we explicitly break the symmetry of the Hamiltonian by applying a fictitious local spin-Zeeman field. Instead, we find that the energy inversion is related to the choice of measurement trial in the estimator, where using a high-order CC trial state for measurements may introduce errors that are suppressed when the measurement wave function is restricted to lower excitation subspaces. In particular, measuring the energy with the mean-field reference while guiding the walkers with a CC trial removes the inverted pattern and improves the overall accuracy across the iron–sulfur clusters, with a possible exception for [4Fe-4S] where energies with a CCSDT guide may be less accurate than those guided by CCSD for some broken-symmetry families. Taken together, our findings suggest that the relatively accurate energies obtained with an HF trial state in these systems arise from favorable error cancellation, warranting significant caution about the reliability of phaseless AFQMC with such trials for strongly correlated transition-metal systems of this kind.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"64 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149368312","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":"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}