Thermodynamic Insights into Protein Dynamics and Drug Development
Main Article Content
Abstract
Protein folding and misfolding play central roles in both health and disease, yet traditional structural analyses often fall short in explaining their functional consequences. This manuscript introduces a thermodynamic framework that integrates three molecular dimensions—chemical composition (constitution), stereochemistry (configuration), and conformational flexibility (conformation)—to better understand how proteins maintain function or drift toward dysfunction. By reframing potential energy and entropy as cooperative forces that govern structural transitions, this model provides insight into the dynamic behavior of proteins in physiological and pathological contexts. Correct folding involves a regulated increase in structural order, a reduction in conformational entropy, and a rise in internal potential energy that supports molecular precision. In contrast, disruptions in this balance can lead to misfolded proteins, aggregation, and disease states such as neurodegeneration, cancer, or immune dysfunction. The framework also highlights how flexible, disordered regions within proteins—often overlooked—can be targeted to design more selective, adaptive, and less toxic therapeutics. By linking molecular structure to biological outcome, this perspective offers a clinically relevant lens for advancing drug development, understanding disease mechanisms, and designing precision medicine strategies.
Keywords:
Potential energy, Entropy, Protein conformation, Constitution–Configuration–Conformation, Intrinsically disordered proteins (IDPs), Drug design, Molecular flexibility
Article Details
How to Cite
ALZEER, Jawad.
Thermodynamic Insights into Protein Dynamics and Drug Development.
Medical Research Archives, [S.l.], v. 13, n. 8, aug. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6867>. Date accessed: 05 dec. 2025.
doi: https://doi.org/10.18103/mra.v13i8.6867.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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3. Csizmók V, Follis A, Kriwacki R, Forman‐Kay J. Dynamic protein interaction networks and new structural paradigms in signaling. Chem Rev. 2016;116(11):6424–6462. https://doi.org/10.1021/acs.chemrev.5b00548
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6. Váradi M, Vranken W, Guharoy M, Tompa P. Computational approaches for inferring the functions of intrinsically disordered proteins. Front Mol Biosci. 2015;2:45. https://doi.org/10.3389/fmolb.2015.00045
7. Tenchov R, Zhou Q. Intrinsically disordered proteins: perspective on COVID-19 infection and drug discovery. ACS Infect Dis. 2022;8(3):422–432. https://doi.org/10.1021/acsinfecdis.2c00031
8. Yang X, Zhou P, Shen S, Hu Q, Tian C, Xia A, et al. Entropy drives the ligand recognition in G-protein-coupled receptor subtypes. Proc Natl Acad Sci U S A. 2024;121(30):e2401091121. https://doi.org/10.1073/pnas.2401091121
9. Fernández A, Fraser C, Scott LR. Purposely engineered drug-target mismatches for entropy-based drug optimization. Trends Biotechnol. 2012;30(1):1–7. https://doi.org/10.1016/j.tibtech.2011.07.003
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12. Sun C, Feng Y, Fan G. IDPsBind: A repository of binding sites for intrinsically disordered protein complexes with known 3D structures. BMC Mol Cell Biol. 2022;23(1):1. https://doi.org/10.1186/s12860-022-00434-5
13. Alzeer J. Directionality of chemical reaction and spontaneity of biological process in the context of entropy. Int J Regen Med. 2022;5(2):1–7. https://doi.org/10.31487/j.rgm.2022.02.06
14. Alzeer J. Exploring the dynamics of nucleophilic substitution reactions: Understanding the role of entropy and potential energy in SN1 and SN2 pathways. Am J Med Chem. 2023;4(1):1–4. https://doi.org/10.31487/j.ajmc.2023.01.02
15. Chalikian T. Hydrophobic tendencies of polar groups as a major force in molecular recognition. Biopolymers. 2003;70(4):492–496. https://doi.org/10.1002/bip.10538
16. Papaleo E, Saladino G, Lambrughi M, Lindorff‐Larsen K, Gervasio F, Nussinov R. The role of protein loops and linkers in conformational dynamics and allostery. Chem Rev. 2016;116(11):6391–6423. https://doi.org/10.1021/acs.chemrev.5b00623
17. Campbell E, Kaltenbach M, Correy G, Carr P, Porebski B, Livingstone E, et al. The role of protein dynamics in the evolution of new enzyme function. Nat Chem Biol. 2016;12(11):944–950. https://doi.org/10.1038/nchembio.2175
18. Dhusia K, Su Z, Wu Y. Understanding the impacts of conformational dynamics on the regulation of protein–protein association by a multiscale simulation method. J Chem Theory Comput. 2020;16(8):5323–5333. https://doi.org/10.1021/acs.jctc.0c00439
19. Bellissent-Funel MC, Hassanali A, Havenith M, Henchman R, Pohl P, Sterpone F, et al. Water determines the structure and dynamics of proteins. Chem Rev. 2016;116(13):7673–7697. https://doi.org/10.1021/acs.chemrev.5b00664
20. Deng N, Zhang P, Cieplak P, Lai L. Elucidating the energetics of entropically driven protein–ligand association: Calculations of absolute binding free energy and entropy. J Phys Chem B. 2011;115(41):11902–11910. https://doi.org/10.1021/jp204047b
21. Strub C, Alies C, Lougarre A, Ladurantie C, Czaplicki J, Fournier D. Mutation of exposed hydrophobic amino acids to arginine to increase protein stability. BMC Biochem. 2004;5(1):9. https://doi.org/10.1186/1471-2091-5-9
22. Dasgupta B, Tiwari S. Explicit versus implicit consideration of binding partners in protein–protein complex to elucidate intrinsic dynamics. Biophys Rev. 2022;14(6):1379–1392. https://doi.org/10.1007/s12551-022-01026-5
23. Bah A, Vernon R, Siddiqui Z, Krzeminski M, Muhandiram R, Zhao C, et al. Folding of an intrinsically disordered protein by phosphorylation as a regulatory switch. Nature. 2014;519(7541):106–109. https://doi.org/10.1038/nature13999
24. Uversky V, Dunker A. Understanding protein non-folding. Biochim Biophys Acta Proteins Proteom. 2010;1804(6):1231–1264. https://doi.org/10.1016/j.bbapap.2010.01.017
25. Uversky V. Functional roles of transiently and intrinsically disordered regions within proteins. FEBS J. 2015;282(7):1182–1189. https://doi.org/10.1111/febs.13202
26. Deiana A, Forcelloni S, Porrello A, Giansanti A. Intrinsically disordered proteins and structured proteins with intrinsically disordered regions have different functional roles in the cell. PLoS One. 2019;14(8):e0217889. https://doi.org/10.1371/journal.pone.0217889.
27. DeForte S, Uversky V. Resolving the ambiguity: making sense of intrinsic disorder when PDB structures disagree. Protein Sci. 2016;25(3):676-688. https://doi.org/10.1002/pro.2864.
28. Korneta I, Bujnicki J. Intrinsic disorder in the human spliceosomal proteome. PLoS Comput Biol. 2012;8(8):e1002641. https://doi.org/10.1371/journal.pcbi.1002641.
29. Sotomayor-Pérez A, Ladant D, Chenal A. Calcium-induced folding of intrinsically disordered repeat-in-toxin (RTX) motifs via changes of protein charges and oligomerization states. J Biol Chem. 2011;286(19):16997-17004. https://doi.org/10.1074/jbc.M110.210393.
30. Miranda-Nieves D, Chaikof E. Collagen and elastin biomaterials for the fabrication of engineered living tissues. ACS Biomater Sci Eng. 2016;3(5):694-711. https://doi.org/10.1021/acsbiomaterials.6b00250.
31. Shoulders MD, Raines RT. Collagen structure and stability. Annu Rev Biochem. 2009;78:929-958. https://doi.org/10.1146/annurev.biochem.77.032207.120833.
32. Dalla Valle L, Nardi A, Alibardi L. Isolation of a new class of cysteine-glycine-proline-rich beta-proteins (beta-keratins) and their expression in snake epidermis. J Anat. 2010;216(3):356-367. https://doi.org/10.1111/j.1469-7580.2009.01192.x.
33. Nguyen T, Bashur C, Kishore V. Impact of elastin incorporation into electrochemically aligned collagen fibers on mechanical properties and smooth muscle cell phenotype. Biomed Mater. 2016;11(2):025008. https://doi.org/10.1088/1748-6041/11/2/025008.
34. Casey D, Jawde S, Herrmann J, Mori V, Mahoney J, Suki B, et al. Percolation of collagen stress in a random network model of the alveolar wall. Sci Rep. 2021;11(1):95911. https://doi.org/10.1038/s41598-021-95911-w.
35. Henninger H, Valdez W, Scott S, Weiss J. Elastin governs the mechanical response of medial collateral ligament under shear and transverse tensile loading. Acta Biomater. 2015;25:304-312. https://doi.org/10.1016/j.actbio.2015.07.011.
36. Munkhuu B, Erdene L, Bayarsukh Z, Altantulga E, Baltsukh O, Tudev G, et al. Antioxidant and antihypertensive activity of collagen and elastin hydrolysate at different molecular weights. Adv Health Care Patient Saf. 2021. https://doi.org/10.2991/ahcps.k.211004.004.
37. Khan AN, Khan RH. Protein misfolding and related human diseases: a comprehensive review of toxicity, proteins involved, and current therapeutic strategies. Int J Biol Macromol. 2022;223(Pt A):143-160. https://doi.org/10.1016/j.ijbiomac.2022.11.031.
38. Quan N, Eguchi Y, Geiler-Samerotte K. Intra-FCY1: a novel system to identify mutations that cause protein misfolding. Front Genet. 2023;14:1198203. https://doi.org/10.3389/fgene.2023.1198203.
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