Journal of Chemical Theory and Computation最新文献

{"title":"Efficient Tensorized Evaluation of Permutation Invariant Polynomials for Representing Potential Energy Surfaces","authors":"Junhong Li,&nbsp;Kaisheng Song,&nbsp;Hua Guo,&nbsp;Jun Li","doi":"10.1021/acs.jctc.6c01659","DOIUrl":"10.1021/acs.jctc.6c01659","url":null,"abstract":"<p>Permutation invariant polynomials (PIPs), together withrelatedpolynomial-based invariant descriptors such as fundamental invariants(FIs), are widely used in constructing high-fidelity global potentialenergy surfaces (PESs) of molecules that contain identical atoms.Although the monomial symmetrization approach (MSA) enables fast evaluationof PIPs through recursive factorization, it leads to deeply nestedcomputational graphs that may require large memory and are inefficientin modern automatic differentiation frameworks. In this work, we introduceJaxPIP, a JAX-based implementation that reformulates PIP/FI evaluationinto tensorized linear algebra operations. By replacing recursivefactorization with dense matrix operations combined with log-exp transformationand segmented summation, the evaluation becomes regular and GPU-friendly.This allows efficient execution with just-in-time compilation andenables large-scale batch evaluation of energies and forces (as wellas higher-order derivatives). The resulting architecture supportsensemble simulations such as quasi-classical trajectory (QCT), path-integralmolecular dynamics (PIMD), and diffusion Monte Carlo (DMC) in a fullyvectorized manner. As demonstrated in examples, JaxPIP provides apractical route for efficient simulations of molecular systems withscalable GPU execution.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"22 19","pages":"9940–9953"},"PeriodicalIF":5.8,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149090871","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":"pGM5P-26: A Polarizable Gaussian Multipole Water Model with Transferable Temperature-Dependent Thermodynamics","authors":"Yongxian Wu,&nbsp;Piotr Cieplak,&nbsp;Yong Duan,&nbsp;Ray Luo","doi":"10.1021/acs.jctc.6c01267","DOIUrl":"10.1021/acs.jctc.6c01267","url":null,"abstract":"<p>Water belongs toa small family of liquids whose density maximumlies above the melting point, a signature of their preference foropen, tetrahedral networks. Reproducing this anomalous density–temperaturecurve, together with ambient thermodynamics, remains a demanding testfor water force fields: fixed-charge models trade 298 K accuracy forlarge errors in ρ(<em>T</em>), while point-multipolepolarizable models must exclude the 1–2 and 1–3 intramolecularcontributions that govern molecular anisotropy and, through nonadditivecoupling, shape the long-range field. We present pGM5P-26, a five-pointpolarizable Gaussian Multipole (pGM) water model whose Gaussian-distributedcharges and dipoles remain finite at all distances, giving a unifiedtreatment of short- and long-range electrostatics that retains theseintramolecular contributions in a fully self-consistent induction.Its 14 independent parameters were optimized exclusively at 298 Kagainst the liquid density, oxygen–oxygen radial distributionfunction, and uncorrected finite-box self-diffusion coefficient usingSMAC Bayesian optimization with Hyperband scheduling. Despite thissingle-temperature training, pGM5P-26 gives the lowest absolute densityRMSE and the second-lowest 298 K-anchored density-shape RMSE amongthe ten simulated models over the out-of-training temperatures from245 to 380 K. Its thermal-expansion curve ranks second by both metrics,and its approximate finite-size-corrected self-diffusion curve ranksthird, placing all three temperature dependences among the closestto experiment in the benchmark set. Its temperature of maximum densityis 280.3 K (experiment: 277.1 K), the second closest after TIP4P/2005.The second virial coefficient reaches near-quantitative agreementwith experiment above 773 K. These results show that Gaussian multipolepolarization combined with automated optimization captures water’sdensity anomaly without explicit temperature-dependent training.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"22 19","pages":"10295–10308"},"PeriodicalIF":5.8,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149091977","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":"Enerzyme: An Efficient Reactive Neural Network Potential Training Framework for Enzyme Cluster Models with Application to Methyltransferases","authors":"Weiliang Luo,Heather J. Kulik","doi":"10.1021/acs.jctc.6c01330","DOIUrl":"https://doi.org/10.1021/acs.jctc.6c01330","url":null,"abstract":"Quantum mechanical (QM) cluster models provide an effective framework for mechanistic studies of enzymatic reactions but QM calculations remain computationally demanding. Neural network potentials (NNPs) offer a promising route to reduce their cost, but enzymes introduce new challenges not faced by NNPs for small molecules, including large system sizes, the need for inclusion of solvent environments, substantial polarization, and charge transfer. Here, we demonstrate an integrated software framework for efficient training of NNPs for mechanistic study of enzymes, with demonstrations on QM-cluster models of S-adenosyl-l-methionine-dependent methyltransferases (MTases). Our Enerzyme code introduces modular, electrostatics-aware NNP architectures and combines automated QM-cluster construction with reactive dataset generation. The Enerzymette subpackage also automates reaction pathway exploration at both NNP and DFT levels of theory. We show that iterative flexible scans and nudged elastic band calculations impose stricter requirements on NNPs than conventionally employed dataset metrics. Nevertheless, we develop an approach to train NNPs on fewer than 1,000 system-specific data points to reproduce reaction energetics and transition-state structures on MTase clusters containing up to 545 atoms, approaching chemical accuracy with respect to the reference. We show that direct supervision of atomic charges and alignment of dielectric screening with QM-cluster calculations substantially improve simulation stability and accuracy and that multitask-learned atomic charges predict correct charge transfer and polarization trends and provide chemically meaningful descriptors of reactivity. Furthermore, we demonstrate transferability across chemically diverse catechol O-methyltransferase substrates, indicating NNPs learn generalizable reactivity patterns as training data is expanded across multiple enzymes. Together, these results establish a foundation for accelerating enzyme mechanistic studies and provide insights for future NNP development for biomolecular reactivity.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"45 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152065","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":"Analyzing Initialization Strategies for the Local Unitary Cluster Jastrow Ansatz within the Quantum-Centric Supercomputing Framework","authors":"Grier M. Jones,&nbsp;Maforikan J. Amoussou,&nbsp;Maximilian O. Leach,&nbsp;Hans-Arno Jacobsen","doi":"10.1021/acs.jctc.6c01195","DOIUrl":"10.1021/acs.jctc.6c01195","url":null,"abstract":"<p>Inthis study, we analyze the choice of local unitary cluster Jastrow(LUCJ) ansatz initialization and the sensitivity of the sample-basedquantum diagonalization (SQD) algorithm within the quantum-centricsupercomputing (QCSC) framework. We examine six initialization strategies,including those based on coupled-cluster singles and doubles (CCSD),Møller–Plesset second-order perturbation theory (MP2),data-driven coupled-cluster (DDCC), and trivial (zeroes and random)initializations, across 12 molecular systems and three basis sets(STO-3G, cc-pVDZ, and aug-cc-pVDZ). We find that while the mean absoluteerrors (MAEs) between the alternative and CCSD-initialized <em>t</em>₂-amplitudes span many orders of magnitude,the resulting SQD energies are largely insensitive to this variation.In particular, most initializations recover energies within chemicalaccuracy (±1.6 m<em>E</em>_h) of the CCSD reference,with convergence improving as the basis set size increases. Notably,random initialization achieves performance competitive with CCSD acrossall basis sets, while initialization with zeroes, despite having smallerdeviations from CCSD, yields the worst energy agreement. Our resultshighlight that the proximity to the CCSD initialization is not a reliablepredictor of the quality of electronic energies. We further show thatremoving configuration recovery entirely increases the average energydeviation from the recovery-corrected result to 18.6 m<em>E</em>_h, and that noiseless statevector sampling of the LUCJwave function is frequently outperformed by noisy hardware sampling,indicating that hardware noise assists configuration recovery by broadeningthe sampled determinant space. These findings establish that configurationrecovery within SQD, rather than circuit initialization, is the dominantfactor governing energy accuracy within the active-space range examinedhere (up to 32 electrons in 26 orbitals), and suggest that computationallycheaper initialization strategies are viable alternatives to CCSDfor QCSC workflows at this scale.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"22 19","pages":"10078–10090"},"PeriodicalIF":5.8,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148973889","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":"Qubit-Adaptive Variational Quantum Imaginary Time Evolution: A Resource-Efficient Algorithm for Ground-State Preparation of Correlated Molecules on Near-Term Quantum Computers","authors":"Thitiwuth Chaiyatho,&nbsp;Zhenyu Li,&nbsp;Jin-Shi Xu,&nbsp;Xiao-Ye Xu,&nbsp;Wiwittawin Sukmas","doi":"10.1021/acs.jctc.6c01171","DOIUrl":"10.1021/acs.jctc.6c01171","url":null,"abstract":"<p>Preparing ground states of correlated molecules on near-termquantumcomputers requires algorithms that are both accurate and resource-efficient.We introduce the qubit-adaptive variational quantum imaginary timeevolution (QAITE) algorithm, which synthesizes the systematic convergenceof imaginary-time evolution with hardware-efficient, adaptive ansatzconstruction. By integrating the linear-scaling qubit operator poolinto the adaptive variational quantum imaginary time evolution framework,QAITE deterministically constructs a compact ansatz without costlyclassical optimization loops. Numerical simulations for molecularsystems (H₄, LiH, H₂O, BeH₂), benchmarkedagainst our own implementations of established adaptive algorithmsunder identical conditions, show that QAITE achieves chemical accuracywith a 15–45% reduction in CNOT gates compared to the standardadaptive variational quantum imaginary time evolution (AVQITE) method.For hydrogen chains (<em>R</em>_HH = 1.5 Å, <em>N</em> = 6–16 qubits), QAITE’s circuit complexitygrows approximately quadratically and remains the lowest of the fourmethods at every system size, reaching 31% fewer CNOT gates than AVQITEat 16 qubits─a saving of 1322 gates. This efficiency extendsto heterogeneous (LiH)_<em>n</em> and (HBe)_<em>n</em> chains, where QAITE maintains a CNOT gateratio below 1 for all sizes studied (e.g., 0.81 for (LiH)₂). We further show that the deterministic parameter update is numericallyrobust: the results are insensitive to the regularization of the quantumgeometric tensor over at least 4 orders of magnitude, and chemicalaccuracy is retained under realistic shot noise applied to both thequantum geometric tensor and the force vector. By outperforming establishedadaptive algorithms in both absolute gate count and scaling, QAITEestablishes a promising, scalable pathway for quantum molecular simulationson noisy intermediate-scale quantum devices.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"22 19","pages":"10091–10100"},"PeriodicalIF":5.8,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149049662","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":"State-Specific Analytical Nuclear Gradients for the Density-Fitted Exact Two-Component State-Averaged Complete Active Space Self-Consistent Field (X2C-SA-CASSCF) Theory","authors":"Saemee Song,&nbsp;Jae Woo Park","doi":"10.1021/acs.jctc.6c01549","DOIUrl":"10.1021/acs.jctc.6c01549","url":null,"abstract":"<p>When a chemical system of interest contains heavy elements,itis important to obtain a balanced description of relativistic effectsand electron correlation. The exact two-component (X2C) Hamiltonianincludes both scalar-relativistic and spin–orbit effects witha reasonable computational cost. By using the spin–orbit X2CHamiltonian in state-averaged complete active space self-consistentfield (SA-CASSCF) calculations, it is possible to obtain equivalentdescriptions of the states with different spin characters. For moleculargeometry optimizations within this framework, the nuclear gradientsshould be efficiently evaluated. In this work, we describe a state-specificanalytical gradient algorithm for X2C-SA-CASSCF theory with the density-fittingapproximation. To realize such calculations, we formulate and implementthe response (<em>Z</em>-vector) equation for X2C-SA-CASSCFtheory. Using the obtained state-specific nuclear gradients, we optimizethe equilibrium geometries of metal porphyrins and the singlet–singletand singlet–triplet minimum energy crossing points or minimumenergy conical intersections of 2-thiouracil.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"22 19","pages":"10203–10212"},"PeriodicalIF":5.8,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149049664","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":"Improving ABFE Calculations for GPCRs by Addressing Errors in Apo-State Representation","authors":"Nithishwer Mouroug Anand,&nbsp;Antonia-Florina Panescu,&nbsp;Ronald M. A. Knegtel,&nbsp;Ewa I. Chudyk,&nbsp;Fabio Zuccotto,&nbsp;Philip C. Biggin","doi":"10.1021/acs.jctc.6c01161","DOIUrl":"10.1021/acs.jctc.6c01161","url":null,"abstract":"<p>Free energy perturbation (FEP) methods provide a robustcomputationalframework for predicting protein-ligand binding affinities and haveseen increased adoption in drug discovery workflows. Among these,absolute binding free energy (ABFE) calculations are especially valuableas they enable affinity prediction for novel compounds without priorexperimental data. However, their broader adoption is limited by setupcomplexity, sampling challenges, and variable performance across systems.These challenges are particularly pronounced in therapeutically relevantcomplex membrane protein systems such as G protein-coupled receptors(GPCRs). This underscores the need to evaluate ABFE performance inGPCR systems and to develop strategies to mitigate these errors. Here,we evaluate ABFE calculations across three GPCR systems: the adenosineA_2A receptor (A_2AR), the dopamine D3 receptor(D3R), and the metabotropic glutamate receptor 5 (mGlu5). We focuson three sources of systematic error in these systems: (i) inadequateresolvation of the binding pocket in apo-like alchemical states, (ii)inconsistent treatment of metal ions, and (iii) insufficient samplingof receptor conformational transitions between holo-like and apo-likeensembles. To address these issues, we introduce two methodologicalimprovements: a biased grand-canonical-like water transport schemeto improve binding pocket resolvation, and a replica-exchange umbrellasampling (REUS)-based framework to quantify and correct the free energyassociated with receptor relaxation to apo-like conformations. Together,these approaches reduce the systematic overestimation of binding affinities,improving agreement with experimental data while maintaining rankingperformance. Overall, our results highlight the importance of accuratelyrepresenting the apo state in ABFE calculations and provide a practicalframework for applying high-accuracy free energy methods to membraneprotein targets.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"22 19","pages":"10428–10444"},"PeriodicalIF":5.8,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149090897","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":"Clifford Disentanglers for Entanglement Reduction in Molecular Electronic Structure Simulations","authors":"Longfei Chang,&nbsp;Zibo Wu,&nbsp;Yunzhi Li,&nbsp;Haiqi Liu,&nbsp;Jiajun Ren,&nbsp;Mingpu Qin,&nbsp;Zhendong Li,&nbsp;Wei-Hai Fang","doi":"10.1021/acs.jctc.6c01170","DOIUrl":"10.1021/acs.jctc.6c01170","url":null,"abstract":"<p>Entanglementis a key bottleneck limiting the efficiency of tensor-networkand quantum simulations of molecular electronic structure. Here, wesystematically assess and extend Clifford disentanglers as a structure-preservingapproach to entanglement reduction: they can modify the entanglementstructure of qubit wave functions while retaining the Pauli-stringform of qubit Hamiltonians. To enable a practical search over Cliffordtransformations, we classify Clifford operators by their action onthe Schmidt spectrum across a bipartition, reducing the two- and four-qubitsearch spaces to 20 and 91392 representatives, respectively. Embeddedin an iterative Clifford-augmented matrix product state framework,these transformations reduce the energy errors at fixed bond dimensionfor the molecular test cases studied and mitigate the dependence onorbital ordering and Fermion-to-qubit mappings. We further show thatClifford disentanglers can also benefit quantum simulations such asshallow-circuit variational quantum eigensolver calculations. Together,these results establish Clifford disentanglers as a useful structure-preservingentanglement-engineering tool for tensor-network and quantum simulationsof molecular electronic structure, while also clarifying their dependenceon correlation and motivating future developments.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"22 19","pages":"10113–10125"},"PeriodicalIF":5.8,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149091935","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":"Dynamic Response Functions for Cavity Quantum Electrodynamics\u0000Hartree–Fock Theory","authors":"Stephen H. Yuwono,Katie A. Crouch,A. Eugene DePrince","doi":"10.1021/acs.jctc.6c01264","DOIUrl":"https://doi.org/10.1021/acs.jctc.6c01264","url":null,"abstract":"Abstract Frequency-dependent linear and quadratic response functions are implemented for a cavity quantum electrodynamics (QED) generalization of Hartree–Fock (HF) theory. Dynamic electric dipole polarizability, optical rectification hyperpolarizability, and second harmonic generation hyperpolarizability tensors are evaluated for molecules strongly coupled to a single-mode optical cavity, and the results are benchmarked against the same tensors obtained from real-time time-dependent QED-HF simulations. Substantial cavity-induced changes to the frequency-dependent properties are observed for certain perturbing frequencies at large electron–photon coupling strengths. We also find special perturbing frequencies at which there is no cavity effect, regardless of the coupling strength.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"24 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149209805","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":"Pathway-Dependent Energetics of SLC15A4–TASL Engagement: Single-Protomer Switching and Dimer-Interface Remodeling","authors":"Xiaoyu Zhao,&nbsp;Danyang Xiong,&nbsp;Feng Gao,&nbsp;Xiao He","doi":"10.1021/acs.jctc.6c01438","DOIUrl":"10.1021/acs.jctc.6c01438","url":null,"abstract":"<p>Membrane-embedded signalosome assembly is co-gated byconformationalselection, oligomeric interfaces, and the lipid microenvironment,yet short-lived, tightly coupled intermediate states are hard to inferfrom static structures. SLC15A4 recruits TASL to support IRF5 signaling,but available structures largely capture distinct conformational endpoints,leaving assembly bottlenecks, interface/lipid coupling, and inhibitorinterception without a quantitative energetic rationale. Here, wedeveloped a computational energetic framework connecting the restingapo dimer to a TASL-permissive state. In the apo state, SLC15A4 maintaineda persistent dimeric arrangement organized around a TM9/TM12-centeredinterfacial scaffold, while the interfacial cholesterol moleculesmaintained persistent contacts with the interface; luminal hydrophobicpacking and a multivalent hydrogen-bond network around N428 were associatedwith interface persistence, while the dimer retained characteristiccoupled motions of MFS helical bundles. Along the prescribed insertionpathway, TASL exhibited a pronounced apparent free-energy rise nearthe pocket, accompanied by rapid contact formation and a single-protomerswitch from luminal-open to cytosolic-open, yielding a modeled asymmetricintermediate with altered cross-protomer interface geometry. TASLwas stabilized by directional anchoring at a few key cationic sites.Pathway-dependent free-energy profiles further indicated that TASLengagement relaxed luminal-side interfacial stabilization and loweredthe free-energy cost of inter-subunit separation without compromisingpocket binding, potentially contributing to the formation of a signaling-competentSLC15A4–TASL module. Finally, our results suggest that an inhibitorlimits access to the TASL-permissive state by locking the luminal-openconformation and occupying the central cavity, increasing the free-energycost along the prescribed TASL entry and reshaping electrostatic determinants.Together, these results connect experimentally resolved structuralstates through a computational energetic framework in which TASL-associatedsingle-protomer switching may couple to luminal interface weakeningand reduced interface persistence, motivating therapeutic strategiestargeting the SLC15A4–TASL–IRF5 axis via conformationallocking and competitive cavity occupation.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"22 19","pages":"10488–10506"},"PeriodicalIF":5.8,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148973850","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}