Hazardous Shortcuts in Standard Binding Free Energy Calculations
Abstract
Calculating the standard binding free energies of protein-protein and protein-ligand complexes from atomistic molecular dynamics simulations in explicit solvent is a problem of central importance in computational biophysics. A rigorous strategy for carrying out such calculations is the so-called "geometrical route". In this method, two molecular objects are progressively separated from one another in the presence of orientational and conformational restraints serving to control the change in configurational entropy that accompanies the dissociation process, thereby allowing the computations to converge within simulations of affordable length. Although the geometrical route provides a rigorous theoretical framework, a tantalizing computational shortcut consists of simply leaving out such orientational and conformational degrees of freedom during the separation process. Here the accuracy and convergence of the two approaches are critically compared in the case of two protein-ligand complexes (Abl kinase-SH3:p41 and MDM2-p53:NVP-CGM097) and three protein-protein complexes (pig insulin dimer, SARS-CoV-2 spike RBD:ACE2, and CheA kinase-P2:CheY). The results of the simulations that strictly follow the geometrical route match the experimental standard binding free energies within chemical accuracy. In contrast, simulations bereft of geometrical restraints converge more poorly, yielding inconsistent results that are at variance with the experimental measurements. Furthermore, the orientational and positional time correlation functions of the protein in the unrestrained simulations decay over several microseconds, a time scale that is far longer than the typical simulation times of the geometrical route, which explains why those simulations fail to sample the relevant degrees of freedom during the separation process of the complexes.
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The term ΔGobulk can be calculated analytically as an angular integral and corresponds to the orientational movement of an unbound partner in the bulk.
“The term ΔGobulk can be calculated analytically as an angular integral (eq 5) and corresponds to the orientational movement of an unbound partner in the bulk.65,67”
From Assessment of the Topology and Oligomerisation States of Coiled Coils Using Metadynamics with Conformational Restraints (2025) · cites this paper as [65]
More precise free energy changes can be obtained through the application of restraints which ensure that the relative orientation and position of the ligand with respect to the receptor is preserved and therefore the available phase space to be sampled during the simulations is reduced.
“More precise free energy changes can be obtained through the application of restraints which ensure that the relative orientation and position of the ligand with respect to the receptor is preserved and therefore the available phase space to be sampled during the simulations is reduced.54,63−65”
From Assessment of the Topology and Oligomerisation States of Coiled Coils Using Metadynamics with Conformational Restraints (2025) · cites this paper as [65]
Simulations without such restraints have been reported to fail to converge and to yield binding free energies inconsistent with experimental data.
“Simulations without such restraints have been reported to fail to converge and to yield binding free energies inconsistent with experimental data.62,65,69”
From Assessment of the Topology and Oligomerisation States of Coiled Coils Using Metadynamics with Conformational Restraints (2025) · cites this paper as [65]
While the path-based PMF approach appears more tractable, it is still difficult to obtain converged free energy estimates for large biomolecules with complex geometries.
“While the path-based PMF approach appears more tractable, it is still difficult to obtain converged free energy estimates for large biomolecules with complex geometries.53,62−68”
From Assessment of the Topology and Oligomerisation States of Coiled Coils Using Metadynamics with Conformational Restraints (2025) · cites this paper as [65]
Cites
Comparison of simple potential functions for simulating liquid water
Jorgensen, W. L., Chandrasekhar, J., Madura, J., Impey, R., & Klein, M. (1983) · The Journal of Chemical Physics · doi:10.1063/1.445869 · Cited by 38,335 · see citing works
CHARMM‐GUI: A web‐based graphical user interface for CHARMM
Jo, S., Kim, T., Iyer, V. G., & Im, W. (2008) · Journal of Computational Chemistry · doi:10.1002/jcc.20945 · Cited by 9,284 · see citing works
Vanommeslaeghe, K., Hatcher, E., Acharya, C., Kundu, S., Zhong, S., Shim, J., Darian, E., Guvench, O., Lopes, P. E. M., Vorobyov, I., et al. (2009) · Journal of Computational Chemistry · doi:10.1002/jcc.21367 · Cited by 6,986 · see citing works
CHARMM36m: An Improved Force Field for Folded and Intrinsically Disordered Proteins
Huang, J., Rauscher, S., Nawrocki, G., Ran, T., Feig, M., de Groot, B. L., Grubmüller, H., & MacKerell, A. (2016) · Nature Methods · doi:10.1038/nmeth.4067 · Cited by 6,708 · see citing works
Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor
Lan, J., Ge, J., Yu, J., Shan, S., Zhou, H., Fan, S., Zhang, Q., Shi, X., Wang, Q., Zhang, L., et al. (2020) · Nature · doi:10.1038/s41586-020-2180-5 · Cited by 5,983 · see citing works
The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities
Genheden, S., & Ryde, U. (2015) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2015.1032936 · Cited by 5,636 · see citing works
Nonequilibrium Equality for Free Energy Differences
Jarzynski, C. (1997) · Physical Review Letters · doi:10.1103/physrevlett.78.2690 · Cited by 5,231 · see citing works
Kollman, P. A., Massova, I., Reyes, C., Kuhn, B., Huo, S., Chong, L., Lee, M., Lee, T., Duan, Y., Wang, W., et al. (2000) · Accounts of Chemical Research · doi:10.1021/ar000033j · Cited by 4,978 · see citing works
Lee, J.-M., Cheng, X., Swails, J. M., Yeom, M. S., Eastman, P., Lemkul, J. A., Wei, S., Buckner, J., Jeong, J. C., Qi, Y., et al. (2015) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.5b00935 · Cited by 4,238 · see citing works
High‐Temperature Equation of State by a Perturbation Method. I. Nonpolar Gases
Zwanzig, R. (1954) · The Journal of Chemical Physics · doi:10.1063/1.1740409 · Cited by 2,923 · see citing works
Continuum Solvent Studies of the Stability of DNA, RNA, and Phosphoramidate−DNA Helices
Srinivasan, J., Cheatham, T. E., Cieplak, P., Kollman, P. A., & Case, D. A. (1998) · Journal of the American Chemical Society · doi:10.1021/ja981844+ · Cited by 1,634 · see citing works
Role of Molecular Dynamics and Related Methods in Drug Discovery
Vivo, M. D., Masetti, M., Bottegoni, G., & Cavalli, A. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01684 · Cited by 1,330 · see citing works
Markov models of molecular kinetics: Generation and validation
Prinz, J.-H., Wu, H., Sarich, M., Keller, B., Senne, M., Held, M., Chodera, J. D., Schütte, C., & Noé, F. (2011) · The Journal of Chemical Physics · doi:10.1063/1.3565032 · Cited by 1,275 · see citing works
Free Energy Calculations by the Molecular Mechanics Poisson−Boltzmann Surface Area Method
Homeyer, N., & Gohlke, H. (2012) · Molecular Informatics · doi:10.1002/minf.201100135 · Cited by 1,170 · see citing works
Steered molecular dynamics and mechanical functions of proteins
Isralewitz, B., Gao, M., & Schulten, K. J. (2001) · Current Opinion in Structural Biology · doi:10.1016/s0959-440x(00)00194-9 · Cited by 1,069 · see citing works
Massova, I., & Kollman, P. A. (2000) · Perspectives in Drug Discovery and Design · doi:10.1023/a:1008763014207 · Cited by 1,015 · see citing works
Chipot, C. J., & Pohorille, A. (2007) · Springer series in chemical physics · doi:10.1007/978-3-540-38448-9 · Cited by 911 · see citing works
Self-citationMarkov State Models: From an Art to a Science
Husic, B. E., & Pande, V. S. (2018) · Journal of the American Chemical Society · doi:10.1021/jacs.7b12191 · Cited by 866 · see citing works
Converging free energy estimates: MM‐PB(GB)SA studies on the protein–protein complex Ras–Raf
Gohlke, H., & Case, D. (2004) · Journal of Computational Chemistry · doi:10.1002/jcc.10379 · Cited by 836 · see citing works
Free energy calculation from steered molecular dynamics simulations using Jarzynski’s equality
Park, S., Khalili‐Araghi, F., Tajkhorshid, E., & Schulten, K. J. (2003) · The Journal of Chemical Physics · doi:10.1063/1.1590311 · Cited by 812 · see citing works
Everything you wanted to know about Markov State Models but were afraid to ask
Pande, V. S., Beauchamp, K., & Bowman, G. R. (2010) · Methods · doi:10.1016/j.ymeth.2010.06.002 · Cited by 698 · see citing works
The structure of 2Zn pig insulin crystals at 1.5 Å resolution
Baker, E. N., Blundell, T. L., Cutfield, J. F., Dodson, E. J., Dodson, G. G., Hodgkin, D. M. C., Hubbard, R. E., Isaacs, N. W., Reynolds, C. D., Sakabe, K., et al. (1988) · Philosophical transactions of the Royal Society of London. Series B, Biological sciences · doi:10.1098/rstb.1988.0058 · Cited by 666 · see citing works
Calculation of absolute protein–ligand binding free energy from computer simulations
Woo, H.-J., & Roux, B. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409005102 · Cited by 661 · see citing works
Self-citationComplete reconstruction of an enzyme-inhibitor binding process by molecular dynamics simulations
Buch, I., Giorgino, T., & De Fabritiis, G. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1103547108 · Cited by 655 · see citing works
Alchemical free energy methods for drug discovery: Progress and challenges
Chodera, J., Mobley, D., Shirts, M., Dixon, R. W., Branson, K., & Pande, V. (2011) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2011.01.011 · Cited by 545 · see citing works
Swanson, J. M. J., Henchman, R. H., & McCammon, J. A. (2004) · Biophysical Journal · doi:10.1016/s0006-3495(04)74084-9 · Cited by 522 · see citing works
Izrailev, S., Stepaniants, S. B., Isralewitz, B., Kosztin, D., Lu, H. J., Molnar, F., Wriggers, W. R., & Schulten, K. J. (1999) · Lecture notes in computational science and engineering · doi:10.1007/978-3-642-58360-5_2 · Cited by 474 · see citing works
Transition networks for modeling the kinetics of conformational change in macromolecules.
Noé, F., & Fischer, S. (2008) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2008.01.008 · Cited by 450 · see citing works
Role of diffusion in ligand binding to macromolecules and cell-bound receptors
Shoup, D., & Szabó, A. (1982) · Biophysical Journal · doi:10.1016/s0006-3495(82)84455-x · Cited by 429 · see citing works
Funnel metadynamics as accurate binding free-energy method
Limongelli, V., Bonomi, M., & Parrinello, M. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1303186110 · Cited by 409 · see citing works
Wang, J., Deng, Y., & Roux, B. (2006) · Biophysical Journal · doi:10.1529/biophysj.106.084301 · Cited by 355 · see citing works
Self-citationStandard Binding Free Energies from Computer Simulations: What Is the Best Strategy?
Gumbart, J. C., Roux, B., & Chipot, C. (2013) · Journal of Chemical Theory and Computation · doi:10.1021/ct3008099 · Cited by 343 · see citing works
Self-citationHermans, J., & Wang, L. (1997) · Journal of the American Chemical Society · doi:10.1021/ja963568+ · Cited by 315 · see citing works
Calculation of Standard Binding Free Energies: Aromatic Molecules in the T4 Lysozyme L99A Mutant
Deng, Y., & Roux, B. (2006) · Journal of Chemical Theory and Computation · doi:10.1021/ct060037v · Cited by 289 · see citing works
Self-citationStandard Free Energy of Binding from a One-Dimensional Potential of Mean Force
Doudou, S., Burton, N. A., & Henchman, R. H. (2009) · Journal of Chemical Theory and Computation · doi:10.1021/ct8002354 · Cited by 216 · see citing works
Zoete, V., Meuwly, M., & Karplus, M. (2005) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.20528 · Cited by 212 · see citing works
Efficient Determination of Protein–Protein Standard Binding Free Energies from First Principles
Gumbart, J. C., Roux, B., & Chipot, C. (2013) · Journal of Chemical Theory and Computation · doi:10.1021/ct400273t · Cited by 211 · see citing works
Self-citationAtomic-level characterization of protein–protein association
Pan, A. C., Jacobson, D., Yatsenko, K., Sritharan, D., Weinreich, T. M., & Shaw, D. E. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1815431116 · Cited by 204 · see citing works
Holzer, P., Masuya, K., Furet, P., Kallen, J., Valat-Stachyra, T., Ferretti, S., Berghausen, J., Bouisset-Leonard, M., Buschmann, N., Pissot-Soldermann, C., et al. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b00810 · Cited by 203 · see citing works
Data handling for science and technology
(1982) · Mathematics and Computers in Simulation · doi:10.1016/0378-4754(82)90080-5 · Cited by 197 · see citing works
Pearlman, D. A. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm050306m · Cited by 193 · see citing works
Mobley, D. L., Chodera, J. D., & Dill, K. A. (2007) · Journal of Chemical Theory and Computation · doi:10.1021/ct700032n · Cited by 186 · see citing works
Fu, H., Chen, H., Blazhynska, M., de Lacam, E. G. C., Szczepaniak, F., Pavlova, À., Shao, X., Gumbart, J. C., Dehez, F., Roux, B., et al. (2022) · Nature Protocols · doi:10.1038/s41596-021-00676-1 · Cited by 181 · see citing works
Self-citationFrontiers in free‐energy calculations of biological systems
Chipot, C. J. (2013) · Wiley Interdisciplinary Reviews Computational Molecular Science · doi:10.1002/wcms.1157 · Cited by 170 · see citing works
Self-citationTaming Rugged Free Energy Landscapes Using an Average Force
Fu, H., Shao, X., Cai, W., & Chipot, C. J. (2019) · Accounts of Chemical Research · doi:10.1021/acs.accounts.9b00473 · Cited by 166 · see citing works
Self-citationZooming across the Free-Energy Landscape: Shaving Barriers, and Flooding Valleys
Fu, H., Zhang, H., Chen, H., Shao, X., Chipot, C. J., & Cai, W. (2018) · The Journal of Physical Chemistry Letters · doi:10.1021/acs.jpclett.8b01994 · Cited by 149 · see citing works
Self-citationDeng, Y., & Roux, B. (2008) · Journal of Chemical Physics · doi:10.1063/1.2842080 · Cited by 139 · see citing works
Self-citationWhat determines the strength of noncovalent association of ligands to proteins in aqueous solution?
Miyamoto, S., & Kollman, P. A. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.18.8402 · Cited by 137 · see citing works
Pisabarro, M. T., Serrano, L. G., & Wilmanns, M. (1998) · Journal of Molecular Biology · doi:10.1006/jmbi.1998.1932 · Cited by 115 · see citing works
Dixit, S. B., & Chipot, C. J. (2001) · The Journal of Physical Chemistry A · doi:10.1021/jp011878v · Cited by 110 · see citing works
Self-citationBaştuğ, T., Chen, P., Patra, S. M., & Serdar Kuyucak, B. (2008) · The Journal of Chemical Physics · doi:10.1063/1.2904461 · Cited by 107 · see citing works
Woods, C. J., Malaisree, M., Hannongbua, S. V., & Mulholland, A. J. (2011) · The Journal of Chemical Physics · doi:10.1063/1.3519057 · Cited by 97 · see citing works
Molecular dynamics and Monte Carlo simulations for protein–ligand binding and inhibitor design
Cole, D. J., Tirado‐Rives, J., & Jorgensen, W. L. (2014) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2014.08.018 · Cited by 90 · see citing works
BFEE2: Automated, Streamlined, and Accurate Absolute Binding Free-Energy Calculations
Fu, H., Chen, H., Cai, W., Shao, X., & Chipot, C. (2021) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.1c00269 · Cited by 83 · see citing works
Self-citationNew Coarse Variables for the Accurate Determination of Standard Binding Free Energies
Fu, H., Cai, W., Hénin, J., Roux, B., & Chipot, C. (2017) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.7b00791 · Cited by 74 · see citing works
Self-citationFrancés‐Monerris, A., Hognon, C., Miclot, T., García‐Iriepa, C., Iriepa, I., Terenzi, A., Grandemange, S., Barone, G., Marazzi, M., & Monari, A. (2020) · Journal of Proteome Research · doi:10.1021/acs.jproteome.0c00779 · Cited by 70 · see citing works
Heinzelmann, G., Henriksen, N. M., & Gilson, M. K. (2017) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.7b00275 · Cited by 69 · see citing works
Ensemble-Based Steered Molecular Dynamics Predicts Relative Residence Time of A2A Receptor Binders
Potterton, A., Husseini, F. S., Southey, M. W. Y., Bodkin, M. J., Heifetz, A., Coveney, P. V., & Townsend‐Nicholson, A. (2019) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.8b01270 · Cited by 60 · see citing works
Evaluation of Predicted Protein–Protein Complexes by Binding Free Energy Simulations
Siebenmorgen, T., & Zacharias, M. (2019) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.8b01022 · Cited by 59 · see citing works
Park, S.-Y., Beel, B. D., Simon, M. I., Bilwes, A. M., & Crane, B. R. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0401038101 · Cited by 58 · see citing works
Chipot, C. J., Kollman, P. A., & Pearlman, D. A. (1996) · Journal of Computational Chemistry · doi:10.1002/(sici)1096-987x(19960715)17:9 · Cited by 58 · see citing works
Self-citationWang, J., Ishchenko, A., Zhang, W., Razavi, A., & Langley, D. (2022) · Scientific Reports · doi:10.1038/s41598-022-05875-8 · Cited by 55 · see citing works
CHARMM-GUI Free Energy Calculator for Practical Ligand Binding Free Energy Simulations with AMBER
Zhang, H., Kim, S., Giese, T. J., Lee, T.-S., Lee, J.-M., York, D., & Im, W. (2021) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.1c00747 · Cited by 52 · see citing works
Yang, L., Zou, J., Xie, H., Li, L., Wei, Y.-Q., & Yang, S. (2009) · PLoS ONE · doi:10.1371/journal.pone.0008470 · Cited by 49 · see citing works
A possible mechanism for concentrating sodium and potassium in the cell nucleus
Moore, R. D., & Morrill, G. A. (1976) · Biophysical Journal · doi:10.1016/s0006-3495(76)85707-4 · Cited by 49 · see citing works
Patel, J. S., & Ytreberg, F. M. (2017) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.7b00660 · Cited by 48 · see citing works
Chaperoned alchemical free energy simulations: A general method for QM, MM, and QM/MM potentials
Yang, W. Y., Bitetti-Putzer, R., & Karplus, M. (2004) · The Journal of Chemical Physics · doi:10.1063/1.1738106 · Cited by 40 · see citing works
García‐Iriepa, C., Hognon, C., Francés‐Monerris, A., Iriepa, I., Miclot, T., Barone, G., Monari, A., & Marazzi, M. (2020) · The Journal of Physical Chemistry Letters · doi:10.1021/acs.jpclett.0c02203 · Cited by 40 · see citing works
Perthold, J. W., & Oostenbrink, C. (2017) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.7b00706 · Cited by 34 · see citing works
Niu, Y., Shi, D., Li, L., Guo, J., Liu, H., & Yao, X. (2017) · Scientific Reports · doi:10.1038/srep46547 · Cited by 33 · see citing works
Exploring the Free-Energy Landscape and Thermodynamics of Protein-Protein Association
Tse, C., Wickstrom, L., Kvaratskhelia, M., Gallicchio, E., Levy, R. M., & Deng, N. (2020) · Biophysical Journal · doi:10.1016/j.bpj.2020.08.005 · Cited by 30 · see citing works
Hu, F., Liu, X., Zhang, J., Zheng, Q., Eglitis, R. I., & Zhang, H. (2019) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.8b00844 · Cited by 27 · see citing works
Gu, J., Li, H., & Wang, X. (2015) · Molecules · doi:10.3390/molecules201019236 · Cited by 24 · see citing works
Zuo, Z., Wang, B., Weng, J., & Wang, W. (2015) · Scientific Reports · doi:10.1038/srep13905 · Cited by 21 · see citing works
Joshi, D. C., & Lin, J. (2019) · Journal of Computational Chemistry · doi:10.1002/jcc.25821 · Cited by 20 · see citing works
Calculating the absolute binding free energy of the insulin dimer in an explicit solvent
Gong, Q., Zhang, H., Zhang, H., & Chen, C. (2020) · RSC Advances · doi:10.1039/c9ra08284k · Cited by 19 · see citing works
Alvarez, L. H., Junior, A. B. D. O., González, J. E. H., Chahine, J., Pascutti, P. G., de Araújo, A. S., & de Souza, F. P. (2021) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2021.03.036 · Cited by 13 · see citing works
Conformational dynamics and free energy of BHRF1 binding to Bim BH3
Lapelosa, M. (2017) · Biophysical Chemistry · doi:10.1016/j.bpc.2017.11.001 · Cited by 12 · see citing works
Jin, X., Bai, Q., Xue, W., Liu, H., & Yao, X. (2015) · Chemometrics and Intelligent Laboratory Systems · doi:10.1016/j.chemolab.2015.10.013 · Cited by 4 · see citing works
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Jhaveri, A., Chhibber, S., Kulkarni, N., & Johnson, M. E. (2025) · The Journal of Chemical Physics · doi:10.1063/5.0275282 · Cited by 4 · see citing works
Notari, E., Wood, C. W., & Michel, J. (2025) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.4c01695 · Cited by 4 · see citing works
“Preliminary metadynamics simulations of the coiled-coil dimers CC-Di and apCC-Di in the absence of restraints (with the exception of the helical ϕ , ψ restraints) yielded similar results to those reported by Blazhynska et al. 65,69 when running unrestrained PMF calculations for protein − protein complexes, namely limi…”
InfluentialBinding Free Energy Calculations Based on the Path Collective Variable along a String Pathway
Ghidini, A., Cavalli, A., & Roux, B. (2025) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.5c02258 · Cited by 2 · see citing works
Self-citationDo all roads lead to Rome? Convergence issues in umbrella sampling simulationsPreprint
Aho, N., Groenhof, G., & Buslaev, P. (2023) · ChemRxiv · doi:10.26434/chemrxiv-2023-2pqls
Notari, E., Wood, C. W., & Michel, J. (2024) · ChemRxiv · doi:10.26434/chemrxiv-2024-t02df
Binding affinities for 2D protein dimerization benefit from enthalpic stabilizationPreprint
Jhaveri, A., Chhibber, S., Kulkarni, N., & Johnson, M. E. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.01.16.633485
Zhang, C., Li, M., Ma, J., Wang, Y., Song, Z., & Wang, X. (2026) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.6c03569
Bases moléculaire de l'interaction protéine-protéine lors de la synaptogenèse
de Lacam, E. G. C. (2023) · theses.fr (ABES) · doi:10.70675/6f0af6e8z43cdz4f3czb462z86c0726d15b4
Modeling and Standard Binding Free Energy Calculations of Complex Biological Objects
Blazhynska, M. (2023) · theses.fr (ABES) · doi:10.70675/48e8ac59z3fecz4841za036z40e6a446b0cc
Self-citationControlled Blood-Brain Barrier Modulation by a High-Affinity Claudin-5 Peptide BinderPreprint
Berselli, A., Trevisani, M., Alberini, G., Pastore, A., Fonzo, A. D., Armirotti, A., Castagnola, V., Maragliano, L., & Benfenati, F. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.09.12.751133
- Authors
- Blazhynska, M., Goulard Coderc de Lacam, E., Chen, H., Roux, B., & Chipot, C.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Laboratoire International Associé Centre National de la Recherche Scientifique et University of Illinois at Urbana−Champaign, Unité Mixte de Recherche 7019, Université de Lorraine, B.P. 70239, 54506 Vandœuvre-lès-Nancy Cedex, France
- Department of Biochemistry and Molecular Biology, The University of Chicago, 929 East 57th Street, W225, Chicago, Illinois 60637, United States
- Corresponding author
- Chipot, Christophe
- Venue
- The Journal of Physical Chemistry Letters
- Publisher
- American Chemical Society (ACS)
- Published
- 2022-06-30
- Volume
- 13
- Issue
- 27
- Pages
- 6250-6258
- ISSN
- 1948-7185 (ISSN-L)
- OpenAlex
- W4283726481
- Cited by
- 27
- References
- 79
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 7 · 2023: 11 · 2022: 1
- FWCI
- 0.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- The Journal of Physical Chemistry Letters (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Agence Nationale de la Recherche
- Division of Molecular and Cellular Biosciences (MCB-1517221)
- France and Chicago Collaborating in the Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Physical Sciences › Chemistry › Physical and Theoretical Chemistry › Advanced Physical and Chemical Molecular Interactions
- Keywords
- protein-protein complex, protein-ligand complex, configurational entropy, conformational restraints, insulin dimer, ACE2, CheA kinase, CheY, time correlation functions, dissociation
- MeSH terms
- COVID-19, SARS-CoV-2, Animals, Ligands, Protein Binding, Proteins, Swine, Thermodynamics, Entropy, Molecular Dynamics Simulation
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