Synchronized motion of interface residues for evaluating protein-RNA complex binding affinity: Application to aptamer-mediated inhibition of TDP-43 aggregates

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• dc.contributor.author Panei, Francesco Paolo
• dc.contributor.author Di Rienzo, Lorenzo
• dc.contributor.author Zacco, Elsa
• dc.contributor.author Armaos, Alexandros, 1989-
• dc.contributor.author Tartaglia, Gian Gaetano
• dc.contributor.author Ruocco, Giancarlo
• dc.contributor.author Milanetti, Edoardo
• dc.date.accessioned 2025-01-31T07:55:53Z
• dc.date.available 2025-01-31T07:55:53Z
• dc.date.issued 2024
• dc.description.abstract Investigating the binding between proteins and aptamers, such as peptides or RNA molecules, is of crucial importance both for understanding the molecular mechanisms that regulate cellular activities and for therapeutic applications in several pathologies. Here, a new computational procedure, employing mainly docking, clustering analysis, and molecular dynamics simulations, was designed to estimate the binding affinities between a protein and some RNA aptamers, through the investigation of the dynamical behavior of the predicted molecular complex. Using the state-of-the-art software catRAPID, we computationally designed a set of RNA aptamers interacting with the TAR DNA-binding protein 43 (TDP-43), a protein associated with several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). We thus devised a computational protocol to predict the RNA-protein molecular complex, so that the structural and dynamical behavior of such a complex can be investigated through extensive molecular dynamics simulation. We hypothesized that the coordinated and synchronized motion of the protein-binding residues, when in contact with RNA molecule, is a critical requisite in order to have a stable binding. Indeed, we calculated the motion covariance exhibited by the interface residues during molecular dynamics simulation: we tested the results against experimental measurements of binding affinity (in this case, the dissociation constant) for six RNA molecules, resulting in a linear correlation of about 0.9. Our findings suggest that the synchronized movement of interface residues plays a pivotal role in ensuring the stability within RNA-protein complexes, moreover providing insights into the contribution of each interface residue. This promising pipeline could thus contribute to the design of RNA aptamers interacting with proteins.
• dc.description.sponsorship This research was partially funded by grants from ERC-2019-Synergy Grant (ASTRA, n. 855923); EIC-2022-PathfinderOpen (ivBM-4PAP, n. 101098989); and Project “National Center for Gene Therapy and Drugs Based on RNA Technology” (CN00000041) financed by NextGeneration EU PNRR MUR—M4C2—Action 1.4—Call “Potenziamento Strutture di Ricerca e Creazione di Campioni Nazionali Di R&S” (CUP J33C22001130001).
• dc.format.mimetype application/pdf
• dc.identifier.citation Panei FP, Di Rienzo L, Zacco E, Armaos A, Tartaglia GG, Ruocco G, et al. Synchronized motion of interface residues for evaluating protein-RNA complex binding affinity: Application to aptamer-mediated inhibition of TDP-43 aggregates. Protein Sci. 2024 Dec;33(12):e5201. DOI: 10.1002/pro.5201
• dc.identifier.doi http://dx.doi.org/10.1002/pro.5201
• dc.identifier.issn 0961-8368
• dc.identifier.uri http://hdl.handle.net/10230/69407
• dc.language.iso eng
• dc.publisher Wiley
• dc.relation.ispartof Protein Sci. 2024 Dec;33(12):e5201
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/855923
• dc.relation.projectID info:eu-repo/grantAgreement/EC/HE/101098989
• dc.rights © 2024 The Author(s). Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc/4.0/
• dc.subject.keyword Binding affinity prediction
• dc.subject.keyword Computational method
• dc.subject.keyword Computational molecular biophysics
• dc.subject.keyword Molecular dynamics simulations
• dc.subject.keyword Protein–RNA interactions
• dc.subject.keyword Synchronized motion
• dc.title Synchronized motion of interface residues for evaluating protein-RNA complex binding affinity: Application to aptamer-mediated inhibition of TDP-43 aggregates
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion