Understanding the conformational dynamics of an intrinsically disordered protein bound to a small molecule

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dc.contributor.authorSharma, Bablien_US
dc.contributor.authorMattaparthi, Venkata Satish Kumaren_US
dc.date.accessioned2025-08-13T11:17:15Z
dc.date.available2025-08-13T11:17:15Z
dc.date.issued2025-07
dc.description.abstractIntrinsically disordered proteins (IDPs) have been implicated in a wide range of human diseases. Due to their intrinsic conformational variability, IDPs are generally not effective for conventional structure-based drug design. Recently, ZZW-115 has been identified as a promising inhibitor of NUPR1 (an IDP whose overexpression is involved in various cancers), offering a potential lead for the development of novel cancer therapies. Understanding the conformational dynamics is crucial for comprehending the inhibitory action of ZZW-115, revealing the binding modes and dynamic interactions between ZZW-115 and NUPR1. Here, we present a computational study employing atomic-level Molecular dynamics (MD) simulations coupled with Umbrella sampling (US) to investigate the binding of ZZW-115 to NUPR1, elucidating the conformational changes and dynamics involved in the interaction. The Potential of Mean Force (PMF) plot showed a minimum value of 9Å at NUPR1-ZZW-115 separation with a dissociation energy of 2 kcal/mol. From Root Mean Square Deviation (RMSD) and secondary structure analysis, the conformational dynamics of NUPR1 was found to be varied as a function of its centre of mass (CoM) distance from ZZW-115. The NUPR1-ZZW-115 complex with the lowest potential energy extracted from the PMF plot was used to study the conformational dynamics of NUPR1 in unbound and complex form. The study reveals specific residues and binding pockets in NUPR1's disordered region that bind to ZZW-115, providing valuable insights into its inhibitory mechanism, enabling the development of effective drug design for therapeutic purposes.en_US
dc.identifier.affiliationsMolecular Modelling and Simulation Laboratory, Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur-784 028, Assam, Indiaen_US
dc.identifier.affiliationsMolecular Modelling and Simulation Laboratory, Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur-784 028, Assam, Indiaen_US
dc.identifier.citationSharma Babli, Mattaparthi Venkata Satish Kumar . Understanding the conformational dynamics of an intrinsically disordered protein bound to a small molecule . Indian Journal of Biochemistry & Biophysics. 2025 Jul; 62(7): 712-723en_US
dc.identifier.issn0301-1208
dc.identifier.issn0975-0959
dc.identifier.placeIndiaen_US
dc.identifier.urihttps://imsear.searo.who.int/handle/123456789/253469
dc.languageenen_US
dc.publisherCSIR-National Institute of Science Communication and Policy Research (NIScPR)en_US
dc.relation.issuenumber7en_US
dc.relation.volume62en_US
dc.source.urihttps://doi.org/10.56042/ijbb.v62i7.13213en_US
dc.subjectMolecular dynamics simulationsen_US
dc.subjectUmbrella samplingen_US
dc.subjectPotential of mean forceen_US
dc.subjectBinding pocketen_US
dc.titleUnderstanding the conformational dynamics of an intrinsically disordered protein bound to a small moleculeen_US
dc.typeJournal Articleen_US
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