{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T19:17:49Z","timestamp":1787944669020,"version":"build-2784847793"},"reference-count":99,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Accurate coordinates for a represented protein state do not, by themselves, establish activity or any other condition-specific function. This article defines the Dynamic Protein Structure Paradox (DPSP) as the apparent conflict between structural accuracy and functional underdetermination and develops it as an integrative evidentiary assessment framework rather than a new theory or paradigm. The underlying problem has been longstanding, since structural genomics, function annotation, allostery, and disorder research each established that fold does not determine function and that function does not determine fold. DPSP consolidates those results into one endpoint-conditioned rule. Once a measurable endpoint is defined, it assesses four coupled dimensions: relevant-state completeness, context completeness, ensemble or kinetic dependence, and chemical dependence. A rubric rates each dimension as adequate, uncertain, or missing, and a materiality test determines which gaps influence the stated decision. The outcome is one of three mutually exclusive modes of utilization: geometry-led, conditional, or function-measured. The deliverable is a concise evidence statement delineating what the structure supports, which decisive variable remains unmeasured, and what corroboration is necessary. DPSP complements, rather than replaces, existing structural, ensemble, and computational approaches. The framework remains unvalidated, its thresholds are provisional, and the studies necessary to confirm or refute it are specified.<\/jats:p>","DOI":"10.3390\/cells15171560","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T18:33:52Z","timestamp":1787942032000},"page":"1560","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dynamic Protein Structure Paradox: An Integrative Framework for Endpoint-Conditioned Evidentiary Sufficiency in Structure-to-Function Claims"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0513-0336","authenticated-orcid":false,"given":"Sarfaraz K.","family":"Niazi","sequence":"first","affiliation":[{"name":"College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA 99202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1038\/181662a0","article-title":"A three-dimensional model of the myoglobin molecule obtained by X-ray analysis","volume":"181","author":"Kendrew","year":"1958","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1126\/science.abj8754","article-title":"Accurate prediction of protein structures and interactions using a three-track neural network","volume":"373","author":"Baek","year":"2021","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1126\/science.ade2574","article-title":"Evolutionary-scale prediction of atomic-level protein structure with a language model","volume":"379","author":"Lin","year":"2023","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate structure prediction of biomolecular interactions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1017\/S0033583503003901","article-title":"Prediction of protein function from protein sequence and structure","volume":"36","author":"Whisstock","year":"2003","journal-title":"Q. Rev. Biophys."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1038\/372631a0","article-title":"Protein superfamilies and domain superfolds","volume":"372","author":"Orengo","year":"1994","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1006\/jmbi.2001.4513","article-title":"Evolution of function in protein superfamilies, from a structural perspective","volume":"307","author":"Todd","year":"2001","journal-title":"J. Mol. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/S0968-0004(98)01335-8","article-title":"Moonlighting proteins","volume":"24","author":"Jeffery","year":"1999","journal-title":"Trends Biochem. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10969-016-9201-5","article-title":"The impact of structural genomics: The first quindecennial","volume":"17","author":"Grabowski","year":"2016","journal-title":"J. Struct. Funct. Genom."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.str.2007.12.002","article-title":"Contributions to the NIH-NIGMS Protein Structure Initiative from the PSI Production Centers","volume":"16","author":"Burley","year":"2008","journal-title":"Structure"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.sbi.2005.04.003","article-title":"Predicting protein function from sequence and structural data","volume":"15","author":"Watson","year":"2005","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1126\/science.181.4096.223","article-title":"Principles that govern the folding of protein chains","volume":"181","author":"Anfinsen","year":"1973","journal-title":"Science"},{"key":"ref_15","unstructured":"Debrunner, P., Tsibris, J., and Munck, E. (1969). How to fold graciously. Mossbauer Spectroscopy in Biological Systems, University of Illinois Press."},{"key":"ref_16","unstructured":"U.S. Food and Drug Administration (2026, July 31). Considerations for the Use of Artificial Intelligence to Support Regulatory Decision-Making for Drug and Biological Products: Draft Guidance for Industry and Other Interested Parties, Available online: https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/considerations-use-artificial-intelligence-support-regulatory-decision-making-drug-and-biological."},{"key":"ref_17","unstructured":"(2018). Assessing Credibility of Computational Modeling Through Verification and Validation: Application to Medical Devices (Standard No. ASME V&V 40-2018)."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/nmeth.2340","article-title":"A large-scale evaluation of computational protein function prediction","volume":"10","author":"Radivojac","year":"2013","journal-title":"Nat. Methods"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"De Paolis Kaluza, M.C., Ramola, R., Joshi, P., Piovesan, D., Reade, W., Orchard, S., Martin, M.J., Ignatchenko, A., Rost, B., and Orengo, C.A. (2026). Advances in Protein Function Prediction from the Fifth CAFA Challenge. bioRxiv.","DOI":"10.64898\/2026.04.27.716980"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1093\/bioinformatics\/bty635","article-title":"SKEMPI 2.0: An updated benchmark of changes in protein-protein binding energy, kinetics and thermodynamics upon mutation","volume":"35","author":"Jankauskaite","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1038\/s41594-022-00849-w","article-title":"A structural biology community assessment of AlphaFold2 applications","volume":"29","author":"Akdel","year":"2022","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.sbi.2016.12.004","article-title":"Principles of protein structural ensemble determination","volume":"42","author":"Bonomi","year":"2017","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"eadv9817","DOI":"10.1126\/science.adv9817","article-title":"Scalable emulation of protein equilibrium ensembles with generative deep learning","volume":"389","author":"Lewis","year":"2025","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1126\/science.1219021","article-title":"The protein-folding problem, 50 years on","volume":"338","author":"Dill","year":"2012","journal-title":"Science"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1002\/prot.340210302","article-title":"Funnels, pathways, and the energy landscape of protein folding: A synthesis","volume":"21","author":"Bryngelson","year":"1995","journal-title":"Proteins"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.sbi.2004.01.009","article-title":"Theory of protein folding","volume":"14","author":"Onuchic","year":"2004","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1126\/science.1749933","article-title":"The energy landscapes and motions of proteins","volume":"254","author":"Frauenfelder","year":"1991","journal-title":"Science"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1038\/nature06522","article-title":"Dynamic personalities of proteins","volume":"450","author":"Kern","year":"2007","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"100039","DOI":"10.1016\/j.csbr.2025.100039","article-title":"Quantum Mechanics Paradox in Protein Structure Prediction: Intrinsically Linked to Sequence Yet Independent of It","volume":"2","author":"Niazi","year":"2025","journal-title":"Comput. Struct. Biotechnol. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"100064","DOI":"10.1016\/j.csbr.2025.100064","article-title":"Critical Assessment of AI-Based Protein Structure Prediction: Fundamental Challenges and Future Directions in Drug Discovery","volume":"2","author":"Niazi","year":"2025","journal-title":"Comput. Struct. Biotechnol. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1038\/nchembio.232","article-title":"The role of dynamic conformational ensembles in biomolecular recognition","volume":"5","author":"Boehr","year":"2009","journal-title":"Nat. Chem. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Marks, D.S., Colwell, L.J., Sheridan, R., Hopf, T.A., Pagnani, A., Zecchina, R., and Sander, C. (2011). Protein 3D structure computed from evolutionary sequence variation. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0028766"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"E1293","DOI":"10.1073\/pnas.1111471108","article-title":"Direct-coupling analysis of residue coevolution captures native contacts across many protein families","volume":"108","author":"Morcos","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1126\/science.aah4043","article-title":"Protein structure determination using metagenome sequence data","volume":"355","author":"Ovchinnikov","year":"2017","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1038\/nbt.3769","article-title":"Mutation effects predicted from sequence co-variation","volume":"35","author":"Hopf","year":"2017","journal-title":"Nat. Biotechnol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1126\/science.1124964","article-title":"New tools provide new insights in NMR studies of protein dynamics","volume":"312","author":"Mittermaier","year":"2006","journal-title":"Science"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1039\/C0CS00113A","article-title":"Hydrogen exchange mass spectrometry for studying protein structure and dynamics","volume":"40","author":"Konermann","year":"2011","journal-title":"Chem. Soc. Rev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1038\/s41586-026-10465-z","article-title":"Large-scale discovery, analysis and design of protein energy landscapes","volume":"654","author":"Ferrari","year":"2026","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.sbi.2012.10.008","article-title":"Single-molecule spectroscopy of protein folding dynamics: Expanding scope and timescales","volume":"23","author":"Schuler","year":"2013","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"16247","DOI":"10.1073\/pnas.1111325108","article-title":"Accessing protein conformational ensembles using room-temperature X-ray crystallography","volume":"108","author":"Fraser","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"107702","DOI":"10.1016\/j.jsb.2021.107702","article-title":"3D variability analysis: Resolving continuous flexibility and discrete heterogeneity from single-particle cryo-EM","volume":"213","author":"Punjani","year":"2021","journal-title":"J. Struct. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1126\/science.1187409","article-title":"Atomic-level characterization of the structural dynamics of proteins","volume":"330","author":"Shaw","year":"2010","journal-title":"Science"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"12562","DOI":"10.1073\/pnas.202427399","article-title":"Escaping free-energy minima","volume":"99","author":"Laio","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6733","DOI":"10.1021\/cr400585q","article-title":"Short linear motifs: Ubiquitous and functionally diverse protein interaction modules directing cell regulation","volume":"114","author":"Uyar","year":"2014","journal-title":"Chem. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1016\/j.jmb.2006.07.087","article-title":"Analysis of molecular recognition features (MoRFs)","volume":"362","author":"Mohan","year":"2006","journal-title":"J. Mol. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/nrm3920","article-title":"Intrinsically disordered proteins in cellular signalling and regulation","volume":"16","author":"Wright","year":"2015","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1126\/science.aaw8653","article-title":"Valence and patterning of aromatic residues determine the phase behavior of prion-like domains","volume":"367","author":"Martin","year":"2020","journal-title":"Science"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nrm.2017.7","article-title":"Biomolecular condensates: Organizers of cellular biochemistry","volume":"18","author":"Banani","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1038\/s41592-021-01117-3","article-title":"Critical assessment of protein intrinsic disorder prediction","volume":"18","author":"Necci","year":"2021","journal-title":"Nat. Methods"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"167208","DOI":"10.1016\/j.jmb.2021.167208","article-title":"AlphaFold and implications for intrinsically disordered proteins","volume":"433","author":"Ruff","year":"2021","journal-title":"J. Mol. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/S0022-2836(65)80285-6","article-title":"On the nature of allosteric transitions: A plausible model","volume":"12","author":"Monod","year":"1965","journal-title":"J. Mol. Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1126\/science.1108595","article-title":"Allosteric mechanisms of signal transduction","volume":"308","author":"Changeux","year":"2005","journal-title":"Science"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1021\/acs.chemrev.6b00177","article-title":"GPCR dynamics: Structures in motion","volume":"117","author":"Latorraca","year":"2017","journal-title":"Chem. Rev."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e4353","DOI":"10.1002\/pro.4353","article-title":"AlphaFold2 fails to predict protein fold switching","volume":"31","author":"Chakravarty","year":"2022","journal-title":"Protein Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/S0968-0004(01)01938-7","article-title":"Macromolecular crowding: Obvious but underappreciated","volume":"26","author":"Ellis","year":"2001","journal-title":"Trends Biochem. Sci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1016\/j.tibs.2016.08.013","article-title":"Macromolecular crowding in vitro, in vivo, and in between","volume":"41","author":"Rivas","year":"2016","journal-title":"Trends Biochem. Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1038\/nature10317","article-title":"Molecular chaperones in protein folding and proteostasis","volume":"475","author":"Hartl","year":"2011","journal-title":"Nature"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/nature07839","article-title":"High-resolution multi-dimensional NMR spectroscopy of proteins in human cells","volume":"458","author":"Inomata","year":"2009","journal-title":"Nature"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1038\/nchembio.1202","article-title":"Atomic-resolution monitoring of protein maturation in live human cells by NMR","volume":"9","author":"Banci","year":"2013","journal-title":"Nat. Chem. Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1016\/j.cell.2024.01.034","article-title":"Rapid simulation of glycoprotein structures by grafting and steric exclusion of glycan conformer libraries","volume":"187","author":"Tsai","year":"2024","journal-title":"Cell"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1146\/annurev-biochem-060408-091030","article-title":"Origins of specificity in protein-DNA recognition","volume":"79","author":"Rohs","year":"2010","journal-title":"Annu. Rev. Biochem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/nature08147","article-title":"Emerging roles for lipids in shaping membrane-protein function","volume":"459","author":"Phillips","year":"2009","journal-title":"Nature"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Rosato, A., Valasatava, Y., and Andreini, C. (2016). Minimal functional sites in metalloproteins and their usage in structural bioinformatics. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17050671"},{"key":"ref_64","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_65","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1146\/annurev.biochem.75.103004.142800","article-title":"Relating protein motion to catalysis","volume":"75","author":"Benkovic","year":"2006","journal-title":"Annu. Rev. Biochem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"27035","DOI":"10.1074\/jbc.273.42.27035","article-title":"Electrostatic origin of the catalytic power of enzymes","volume":"273","author":"Warshel","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1038\/nature08615","article-title":"Hidden alternative structures of proline isomerase essential for catalysis","volume":"462","author":"Fraser","year":"2009","journal-title":"Nature"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1126\/science.1260031","article-title":"A protein fold switch joins the circadian oscillator to clock output in cyanobacteria","volume":"349","author":"Chang","year":"2015","journal-title":"Science"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1126\/science.aag3218","article-title":"Structures of the cyanobacterial circadian oscillator frozen in a fully assembled state","volume":"355","author":"Snijder","year":"2017","journal-title":"Science"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1146\/annurev.biophys.27.1.249","article-title":"Inhibitors of HIV-1 protease: A major success of structure-assisted drug design","volume":"27","author":"Wlodawer","year":"1998","journal-title":"Annu. Rev. Biophys. Biomol. Struct."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1080\/19420862.2018.1553476","article-title":"Structure, heterogeneity and developability assessment of therapeutic antibodies","volume":"11","author":"Xu","year":"2019","journal-title":"mAbs"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1016\/j.xphs.2018.11.029","article-title":"The mechanistic impact of N-glycosylation on stability, pharmacokinetics, and immunogenicity of therapeutic proteins","volume":"108","author":"Zhou","year":"2019","journal-title":"J. Pharm. Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1007\/s00775-008-0404-5","article-title":"Metal ions in biological catalysis: From enzyme databases to general principles","volume":"13","author":"Andreini","year":"2008","journal-title":"J. Biol. Inorg. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"D439","DOI":"10.1093\/nar\/gkab1061","article-title":"AlphaFold Protein Structure Database: Massively expanding the structural coverage of protein-sequence space with high-accuracy models","volume":"50","author":"Varadi","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/s41586-021-03828-1","article-title":"Highly accurate protein structure prediction for the human proteome","volume":"596","author":"Tunyasuvunakool","year":"2021","journal-title":"Nature"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2742","DOI":"10.1093\/bioinformatics\/btac202","article-title":"Impact of protein conformational diversity on AlphaFold predictions","volume":"38","author":"Saldano","year":"2022","journal-title":"Bioinformatics"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Tejero, R., Huang, Y.J., Ramelot, T.A., and Montelione, G.T. (2022). AlphaFold models of small proteins rival the accuracy of solution NMR structures. Front. Mol. Biosci., 9.","DOI":"10.3389\/fmolb.2022.877000"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1016\/j.str.2022.04.005","article-title":"The accuracy of protein structures in solution determined by AlphaFold and NMR","volume":"30","author":"Fowler","year":"2022","journal-title":"Structure"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"e75751","DOI":"10.7554\/eLife.75751","article-title":"Sampling alternative conformational states of transporters and receptors with AlphaFold2","volume":"11","author":"Sala","year":"2022","journal-title":"eLife"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1038\/nrd.2016.109","article-title":"Twenty years on: The impact of fragments on drug discovery","volume":"15","author":"Erlanson","year":"2016","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2695","DOI":"10.1021\/ja512751q","article-title":"Accurate and reliable prediction of relative ligand binding potency in prospective drug discovery by way of a modern free-energy calculation protocol and force field","volume":"137","author":"Wang","year":"2015","journal-title":"J. Am. Chem. Soc."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cbpa.2018.05.003","article-title":"Cryptic binding sites on proteins: Definition, detection, and druggability","volume":"44","author":"Vajda","year":"2018","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1124\/pr.112.007336","article-title":"Computational methods in drug discovery","volume":"66","author":"Sliwoski","year":"2014","journal-title":"Pharmacol. Rev."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1038\/nrd1549","article-title":"Docking and scoring in virtual screening for drug discovery","volume":"3","author":"Kitchen","year":"2004","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1017\/S0033583508004708","article-title":"Protein-protein interaction and quaternary structure","volume":"41","author":"Janin","year":"2008","journal-title":"Q. Rev. Biophys."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/S0958-1669(99)00054-3","article-title":"Advances in surface plasmon resonance biosensor analysis","volume":"11","author":"Rich","year":"2000","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1038\/nprot.2006.28","article-title":"Isothermal titration calorimetry to determine association constants for high-affinity ligands","volume":"1","author":"Freire","year":"2006","journal-title":"Nat. Protoc."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1146\/annurev.biophys.36.040306.132550","article-title":"Calculation of protein-ligand binding affinities","volume":"36","author":"Gilson","year":"2007","journal-title":"Annu. Rev. Biophys. Biomol. Struct."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1038\/s41592-021-01098-3","article-title":"Martini 3: A general purpose force field for coarse-grained molecular dynamics","volume":"18","author":"Souza","year":"2021","journal-title":"Nat. Methods"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"3977","DOI":"10.1021\/acs.jctc.0c00188","article-title":"Protein structure prediction in CASP13 using AWSEM-Suite","volume":"16","author":"Jin","year":"2020","journal-title":"J. Chem. Theory Comput."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"W382","DOI":"10.1093\/nar\/gki387","article-title":"The FoldX web server: An online force field","volume":"33","author":"Schymkowitz","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1002\/prot.22921","article-title":"Role of conformational sampling in computing mutation-induced changes in protein structure and stability","volume":"79","author":"Kellogg","year":"2011","journal-title":"Proteins"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"5389","DOI":"10.1021\/acs.jpcb.7b11367","article-title":"Flex ddG: Rosetta ensemble-based estimation of changes in protein-protein binding affinity upon mutation","volume":"122","author":"Barlow","year":"2018","journal-title":"J. Phys. Chem. B"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"159","DOI":"10.2307\/2529310","article-title":"The measurement of observer agreement for categorical data","volume":"33","author":"Landis","year":"1977","journal-title":"Biometrics"},{"key":"ref_95","unstructured":"PDBbind+ (2026, July 31). PDBbind Database, Version 2020 Refined Set (v.2020R1). Available online: https:\/\/www.pdbbind-plus.org.cn\/download."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"4108","DOI":"10.1021\/cr900033p","article-title":"Theory, practice, and applications of paramagnetic relaxation enhancement for the characterization of transient low-population states of biological macromolecules and their complexes","volume":"109","author":"Clore","year":"2009","journal-title":"Chem. Rev."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"98","DOI":"10.3390\/biomedinformatics4010007","article-title":"Limitations of Protein Structure Prediction Algorithms in Therapeutic Protein Development","volume":"4","author":"Niazi","year":"2024","journal-title":"BioMedInformatics"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2603140","DOI":"10.1080\/19420889.2025.2603140","article-title":"Quantum Mechanics in Drug Design: Progress, Challenges, and Future Frontiers","volume":"19","author":"Niazi","year":"2026","journal-title":"Commun. Integr. Biol."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Niazi, S.K. (2026). A Risk-Tiered Validation Framework for Artificial Intelligence in Drug Discovery: From Reproducibility to Clinical Translation. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27104349"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/17\/1560\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T18:41:49Z","timestamp":1787942509000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/17\/1560"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,28]]},"references-count":99,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["cells15171560"],"URL":"https:\/\/doi.org\/10.3390\/cells15171560","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,28]]}}}