{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T02:11:24Z","timestamp":1768270284097,"version":"3.49.0"},"reference-count":88,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2012,8,7]],"date-time":"2012-08-07T00:00:00Z","timestamp":1344297600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Entropy"],"abstract":"<jats:p>Discovering the mechanism that controls the three-dimensional structures of proteins, which are closely related to their biological functions, remains a challenge in modern biological science, even for small proteins. From a thermodynamic viewpoint, the native structure of a protein can be understood as the global minimum of the free energy landscape of the protein-water system. However, it is still difficult to describe the energetics of protein stability in an effective manner. Recently, our group developed a free energy function with an all-atomic description for a protein that focuses on hydration thermodynamics. The validity of the function was examined using structural decoy sets that provide numerous misfolded \u201cnon-native\u201d structures. For all targeted sets, the function was able to identify the experimentally determined native structure as the best structure. The energy function can also be used to calculate the binding free energy of a protein with ligands. I review the physicochemical theories employed in the development of the free energy function and recent studies evaluating protein structure stability and protein-ligand binding affinities that use this function.<\/jats:p>","DOI":"10.3390\/e14081443","type":"journal-article","created":{"date-parts":[[2012,8,7]],"date-time":"2012-08-07T10:56:27Z","timestamp":1344336987000},"page":"1443-1468","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Application of Hydration Thermodynamics to the Evaluation of Protein Structures and Protein-Ligand Binding"],"prefix":"10.3390","volume":"14","author":[{"given":"Yuichi","family":"Harano","sequence":"first","affiliation":[{"name":"Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita-shi, Osaka 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2012,8,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1126\/science.181.4096.223","article-title":"Principles that govern folding of protein chains","volume":"181","author":"Anfinsen","year":"1973","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7133","DOI":"10.1021\/bi00483a001","article-title":"Dominant forces in protein folding","volume":"29","author":"Dill","year":"1990","journal-title":"Biochemistry"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1006\/jmbi.1996.0712","article-title":"Protein binding versus protein folding: The role of hydrophilic bridges in protein associations","volume":"265","author":"Xu","year":"1997","journal-title":"J. Mol. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1002\/pro.5560030206","article-title":"Do salt bridges stabilize proteins: A continuum electrostatic analysis","volume":"3","author":"Hendsch","year":"1994","journal-title":"Protein Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1021\/bi9621829","article-title":"Contribution of the hydrophobic effect to the stability of human lysozyme: Calorimetric studies and X-ray structural analyses of the nine valine to alanine mutants","volume":"36","author":"Takano","year":"1997","journal-title":"Biochemistry"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1021\/bi001574j","article-title":"Polar group burial contribute more to protein stability than nonpolar group burial","volume":"40","author":"Pace","year":"2001","journal-title":"Biochemistry"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"16172","DOI":"10.1021\/bi981788p","article-title":"Mutagenesis of a buried polar interaction in an SH3 domain: Sequence conservation provides the best prediction of stability effects","volume":"37","author":"Maxwell","year":"1998","journal-title":"Biochemistry"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"16096","DOI":"10.1073\/pnas.1004213107","article-title":"Charges in the hydrophobic interior of proteins","volume":"107","author":"Isom","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/s10955-011-0382-9","article-title":"Introduction to special issue on water and associated liquids","volume":"145","author":"Weeks","year":"2011","journal-title":"J. Stat. Phys."},{"key":"ref_10","first-page":"557","article-title":"On the nature of protein interior","volume":"229","author":"Klapper","year":"1971","journal-title":"Biochem. Biophys. Acta"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1006\/jmbi.1999.2829","article-title":"The packing density in proteins: Standard radii and volumes","volume":"290","author":"Tsai","year":"1999","journal-title":"J. Mol. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1006\/jmbi.1998.2374","article-title":"Native proteins are surface-molten solids: Application of the Lindemann criterion for the solid versus liquid state","volume":"285","author":"Zhou","year":"1999","journal-title":"J. Mol. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1006\/jmbi.2000.3750","article-title":"Protein packing: Dependence on protein size, secondary structure and amino acid composition","volume":"299","author":"Fleming","year":"2000","journal-title":"J. Mol. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1002\/jcc.540111014","article-title":"The nature of the N-H O=C hydrogen-bond: An intermolecular perturbation-theory study of the formamide formaldehyde complex","volume":"11","author":"Mitchell","year":"1990","journal-title":"J. Comput. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/0009-2614(91)85003-F","article-title":"On the relative strengths of amide\u2026amide and amide\u2026water hydrogen bonds","volume":"180","author":"Mitchell","year":"1991","journal-title":"Chem. Phys. Lett."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"R17","DOI":"10.1016\/S1359-0278(96)00005-3","article-title":"Adding backbone to protein folding: Why proteins are polypeptides","volume":"1","author":"Honig","year":"1996","journal-title":"Fold. Des."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"17581","DOI":"10.1074\/jbc.X200009200","article-title":"In search of the energetic role of peptide hydrogen bonds","volume":"278","author":"Baldwin","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0065-3233(08)60608-7","article-title":"Some factors in the interpretation of protein denaturation","volume":"14","author":"Kauzmann","year":"1959","journal-title":"Adv. Protein Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1002\/prot.340080104","article-title":"Hydrophobicity of amino acid subgroup in proteins","volume":"8","author":"Lesser","year":"1990","journal-title":"Proteins"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1002\/jcc.10144","article-title":"Methodology of predicting approximate shapes and size distribution of micelles: Illustration for simple models","volume":"23","author":"Kinoshita","year":"2002","journal-title":"J. Comput. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1038\/nature02261","article-title":"Protein folding and misfolding","volume":"426","author":"Dobson","year":"2003","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1002\/pol.1958.1203312618","article-title":"Interaction between particles suspended in solutions of macromolecules","volume":"33","author":"Asakura","year":"1958","journal-title":"J. Polym. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1038\/383239a0","article-title":"Entropic control of particle motion using passive surface microstructure","volume":"383","author":"Dinsmore","year":"1996","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1038\/416811a","article-title":"Insights into phase transition kinetics from colloid science","volume":"416","author":"Anderson","year":"2002","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.cplett.2004.09.140","article-title":"Large gain in translational entropy of water is a major driving force in protein folding","volume":"399","author":"Harano","year":"2004","journal-title":"Chem. Phys. Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2701","DOI":"10.1529\/biophysj.104.057604","article-title":"Translational-entropy gain of solvent upon protein folding","volume":"89","author":"Harano","year":"2005","journal-title":"Biophys. J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2247","DOI":"10.1002\/pro.5560041101","article-title":"Side-chain conformational entropy in protein folding","volume":"4","author":"Doig","year":"1995","journal-title":"Protein Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"78101","DOI":"10.1103\/PhysRevLett.97.078101","article-title":"Morphometric approach to the solvation free energy of complex molecules","volume":"97","author":"Roth","year":"2006","journal-title":"Phys. Rev. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.cplett.2007.01.087","article-title":"Physical basis for characterizing native structures of proteins","volume":"437","author":"Harano","year":"2007","journal-title":"Chem. Phys. Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8165","DOI":"10.1063\/1.473822","article-title":"An investigation of the influence of solute size and insertion conditions on solvation thermodynamics","volume":"106","author":"Cann","year":"1997","journal-title":"J. Chem. Phys."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"244504","DOI":"10.1063\/1.2403873","article-title":"Changes in thermodynamic quantities upon contact of two solutes in solvent under isochoric and isobaric conditions","volume":"125","author":"Kinoshita","year":"2006","journal-title":"J. Chem. Phys."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"024911","DOI":"10.1063\/1.2213980","article-title":"Theoretical analysis on hydration thermodynamics of proteins","volume":"125","author":"Imai","year":"2007","journal-title":"J. Chem. Phys."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"244512","DOI":"10.1063\/1.2137708","article-title":"Pair-correlation entropy of hydrophobic hydration: Decomposition into translational and orientational contributions and analysis of solute-size effects","volume":"124","author":"Kinoshita","year":"2006","journal-title":"J. Chem. Phys."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"225102","DOI":"10.1063\/1.2743962","article-title":"Theoretical analysis on changes in thermodynamic quantities upon protein folding: Essential role of hydration","volume":"126","author":"Imai","year":"2007","journal-title":"J. Chem. Phys."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7715","DOI":"10.1063\/1.454286","article-title":"On the molecular theory of aqueous electrolyte solutions. I. The solution of the RHNC approximation for models in finite concentration","volume":"88","author":"Kusalik","year":"1988","journal-title":"J. Chem. Phys."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1080\/00268978800101631","article-title":"The solution of the reference hypernetted-chain approximation for water-like models","volume":"65","author":"Kusalik","year":"1988","journal-title":"Mol. Phys."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1006\/jcph.1996.0055","article-title":"Analysis of the bulk and surface-induced structure of electrolyte solutions using integral equation theories","volume":"124","author":"Kinoshita","year":"1996","journal-title":"J. Comput. Phys."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"024507","DOI":"10.1063\/1.2823733","article-title":"Molecular origin of the hydrophobic effect: Analysis using the angle-dependent integral equation theory","volume":"128","author":"Kinoshita","year":"2008","journal-title":"J. Chem. Phys."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1023\/B:JOSL.0000043632.91521.59","article-title":"Water structure and phase transition near a surface","volume":"33","author":"Kinoshita","year":"2004","journal-title":"J. Sol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5933","DOI":"10.1021\/jp027815+","article-title":"Polarizable atomic multipole water model for molecular mechanics simulation","volume":"107","author":"Ren","year":"2003","journal-title":"J. Phys. Chem. B"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1143\/PTP.23.829","article-title":"Theory of classical fluids: Hyper-netted chain approximation. III: A new integral equation for the pair distribution function","volume":"23","author":"Morita","year":"1960","journal-title":"Prog. Theor. Phys."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1143\/PTP.25.537","article-title":"A new approach of the theory of classical fluids. III: General treatment of classical systems","volume":"25","author":"Morita","year":"1961","journal-title":"Prog. Theor. Phys."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1126\/science.6879170","article-title":"Solvent-accessible surfaces of proteins and nucleic acids","volume":"221","author":"Connolly","year":"1983","journal-title":"Science"},{"key":"ref_44","first-page":"1","article-title":"Satisfying hydrogen bonding potential in proteins","volume":"132","author":"McDonald","year":"1994","journal-title":"J. Mol. Biol. 1994,"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/0022-2836(89)90609-8","article-title":"Thermodynamics of amide hydrogen bond formation in polar and apolar solvents","volume":"209","author":"Snedon","year":"1989","journal-title":"J. Mol. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1110\/ps.051454805","article-title":"Do all backbone polar groups in proteins form hydrogen bonds?","volume":"14","author":"Fleming","year":"2005","journal-title":"Protein Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1002\/prot.22520","article-title":"Free-energy function based on an all-atom model for proteins","volume":"77","author":"Yoshidome","year":"2009","journal-title":"Proteins"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2161","DOI":"10.1002\/prot.23036","article-title":"Free-energy function for discriminating the native fold of a protein from misfolded decoys","volume":"79","author":"Yasuda","year":"2011","journal-title":"Proteins"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1006\/jmbi.1996.0256","article-title":"Energy functions that discriminates X-ray and near native folds from well-constructed decoys","volume":"258","author":"Park","year":"1996","journal-title":"J. Mol. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1006\/jmbi.1997.0959","article-title":"Assembly of protein tertiary structures from fragments with similar local sequences using simulated annealing and bayesian scoring functions","volume":"268","author":"Simons","year":"1997","journal-title":"J. Mol. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1002\/(SICI)1097-0134(1999)37:3+<171::AID-PROT21>3.0.CO;2-Z","article-title":"Ab initio protein structure prediction of CASP III targets using ROSETTA","volume":"37","author":"Simons","year":"1999","journal-title":"Proteins"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Samudrala, R., Xia, Y., Levitt, M., and Huang, E. S. (1999, January 4\u20139). A combined approach for ab initio construction of low resolution protein tertiary structures from sequence. Proceedings of the Pacific Symposium on Biocomputing, Mauni Lani, Big Island, HI, USA.","DOI":"10.1142\/9789814447300_0050"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1006\/jmbi.2000.3835","article-title":"Ab initio construction of protein tertiary structures using a hierarchical approach","volume":"300","author":"Xia","year":"2000","journal-title":"J. Mol. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/S0022-2836(03)00323-1","article-title":"A novel approach to decoy set generation: Designing a physical energy function having local minima with native structure characteristics","volume":"329","author":"Keasar","year":"2003","journal-title":"J. Mol. Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/1472-6807-2-3","article-title":"A comprehensive analysis of 40 blind protein structure predictions","volume":"2","author":"Samudrala","year":"2002","journal-title":"BMC Struct. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1110\/ps.9.7.1399","article-title":"Decoys \u2018R\u2019 Us: A database of incorrect protein conformations to improve protein structure prediction","volume":"9","author":"Samudrala","year":"2000","journal-title":"Protein Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/0022-2836(91)90754-T","article-title":"Efficient computation of three-dimensional protein structures in solution from nuclear magnetic resonance data using the program DIANA and the supporting programs CALIBA, HABAS and GLOMSA","volume":"217","author":"Braun","year":"1991","journal-title":"J. Mol. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1126\/science.1853201","article-title":"A method to identify protein sequences that fold into a known three-dimensional structure","volume":"253","author":"Bowie","year":"1991","journal-title":"Science"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1007\/BF02337562","article-title":"Boltzmann's principle, knowledge-based mean fields and protein folding. An approach to the computational determination of protein structures","volume":"7","author":"Sippl","year":"1993","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.jmb.2007.11.033","article-title":"OPUS-PSP: An orientation-dependent statistical all-atom potential derived from side-chain packing","volume":"376","author":"Lu","year":"2008","journal-title":"J. Mol. Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"024901:1","DOI":"10.1063\/1.1824012","article-title":"How effective for fold recognition is a potential of mean force that includes relative orientations between contacting residues in proteins?","volume":"122","author":"Miyazawa","year":"2005","journal-title":"J. Chem. Phys."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1002\/prot.10470","article-title":"Distinguish protein decoys by using a scoring function based on a new AMBER force field, short molecular dynamics simulations, and the generalized born solvent model","volume":"55","author":"Lee","year":"2004","journal-title":"Proteins"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1110\/ps.03348304","article-title":"An accurate, residue-level, pair potential of mean force for folding and binding based on the distance-scaled, ideal-gas reference state","volume":"13","author":"Zhang","year":"2004","journal-title":"Protein Sci."},{"key":"ref_64","first-page":"48","article-title":"Using data compression for multidimensional distribution analysis","volume":"17","author":"Onizuka","year":"2002","journal-title":"Control Intell. Syst."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2714","DOI":"10.1110\/ps.0217002","article-title":"Distance-scaled, finite ideal-gas reference state improves structure-derived potentials of mean force for structure selection and stability prediction","volume":"11","author":"Zhou","year":"2002","journal-title":"Protein Sci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1002\/1097-0134(20001001)41:1<40::AID-PROT70>3.0.CO;2-U","article-title":"Distance-dependent, pair potential for protein folding: Results from linear optimization","volume":"41","author":"Toby","year":"2000","journal-title":"Proteins"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3586","DOI":"10.1021\/jp973084f","article-title":"All-atom empirical potential for molecular modeling and dynamics studies of proteins","volume":"102","author":"MacKerell","year":"1998","journal-title":"J. Phys. Chem. B"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1002\/jcc.20065","article-title":"Extending the treatment of backbone energetics in protein force fields: Limitations of gas-phase quantum mechanics in reproducing protein conformational distributions in molecular dynamics simulations","volume":"25","author":"MacKerell","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"10606","DOI":"10.1063\/1.1480013","article-title":"Novel generalized Born methods","volume":"116","author":"Lee","year":"2002","journal-title":"J. Chem. Phys."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1002\/jcc.10272","article-title":"New analytic approximation to the standard molecular volume definition and its application to generalized Born calculations","volume":"24","author":"Lee","year":"2003","journal-title":"J. Comput. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1002\/jcc.20387","article-title":"Balancing an accurate representation of the molecular surface in generalized born formalisms with integrator stability in molecular dynamics simulations","volume":"27","author":"Feig","year":"2006","journal-title":"J. Comput. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"5568","DOI":"10.1063\/1.479860","article-title":"The alanine dipeptide free energy surface in solution","volume":"111","author":"Smith","year":"1999","journal-title":"J. Chem. Phys."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"5064","DOI":"10.1021\/jp022445a","article-title":"Conformational dynamics of trialanine in water. 2. Comparison of AMBER, CHARMM, GROMOS, and OPLS force fields to NMR and infrared experiments","volume":"107","author":"Mu","year":"2003","journal-title":"J. Phys. Chem. B"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1002\/jcc.22891","article-title":"Evaluation of protein-ligand binding free energy focused on its entropic components","volume":"33","author":"Chiba","year":"2012","journal-title":"J. Comput. Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1021\/cr040426m","article-title":"Molecular dynamics: Survey of methods for simulating the activity of proteins","volume":"106","author":"Adcock","year":"2006","journal-title":"Chem. Rev."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1534","DOI":"10.1073\/pnas.0610494104","article-title":"Ligand configurational entropy and protein binding","volume":"104","author":"Chang","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/0009-2614(95)01082-K","article-title":"Pairwise solute descreening of solute charges from a dielectric medium","volume":"246","author":"Hawkins","year":"1995","journal-title":"Chem. Phys. Lett."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/S0968-0896(99)00015-2","article-title":"Estimation of the binding affinities of FKBP12 inhibitors using a linear response method","volume":"7","author":"Lamb","year":"1999","journal-title":"Bioorg. Med. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1002\/prot.21044","article-title":"A computational analysis of the binding affinities of FKBP12 inhibitors using the MM-PB\/SA method","volume":"64","author":"Xu","year":"2006","journal-title":"Proteins"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"084901","DOI":"10.1063\/1.2221680","article-title":"Parallelized-over-parts computation of absolute binding free energy with docking and molecular dynamics","volume":"125","author":"Jayachandran","year":"2006","journal-title":"J. Chem. Phys."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2798","DOI":"10.1529\/biophysj.106.084301","article-title":"Absolute binding free energy calculations using molecular dynamics simulations with restraining potentials","volume":"91","author":"Wang","year":"2006","journal-title":"Biophys. J."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"084108","DOI":"10.1063\/1.1999637","article-title":"Direct calculation of the binding free energies of FKBP ligands","volume":"123","author":"Fujitani","year":"2005","journal-title":"J. Chem. Phys."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"021914","DOI":"10.1103\/PhysRevE.79.021914","article-title":"Massively parallel computation of absolute binding free energy with well-equilibrated states","volume":"79","author":"Fujitani","year":"2009","journal-title":"Phys. Rev. E"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1002\/prot.22176","article-title":"Structural coupling between FKBP12 and buried water","volume":"74","author":"Szep","year":"2009","journal-title":"Proteins"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1964","DOI":"10.1073\/pnas.91.5.1964","article-title":"Enthalpy of hydrogen bond formation in a protein-ligand binding reaction","volume":"91","author":"Connelly","year":"1994","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"9925","DOI":"10.1021\/ja00075a008","article-title":"Design, synthesis, and kinetic evaluation of high-affinity FKBP ligands and the X-ray crystal structures of their complexes with FKBP12","volume":"115","author":"Holt","year":"1993","journal-title":"J. Am. Chem. Soc."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1038\/nchembio.347","article-title":"The role of conformational entropy in molecular recognition by calmodulin","volume":"6","author":"Marlow","year":"2010","journal-title":"Nat. Chem. Biol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"5871","DOI":"10.1021\/jp809968p","article-title":"Entropic cost of protein-ligand binding and its dependence on the entropy in solution","volume":"113","author":"Irudayam","year":"2009","journal-title":"J. Phys. 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