Plasticity and functional modulation of intrinsically disordered proteins

• Grant number: 22/07231-7
• Support Opportunities: Research Projects - Thematic Grants
• Start date: March 01, 2024
• End date: February 28, 2029
• Field of knowledge: Physical Sciences and Mathematics - Physics - Condensed Matter Physics
• Principal Investigator: Vitor Barbanti Pereira Leite
• Grantee: Vitor Barbanti Pereira Leite
• Host Institution: Instituto de Química (IQ). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Pesquisadores principais: Roberto Kopke Salinas ; Rosangela Itri ; Thereza Amélia Soares da Silva
• Associated researchers: Alexandre Suman de Araujo ; Ana Paula Ribeiro Povinelli ; Dayane dos Santos Alvares ; Denys Ewerton da Silva Santos ; Fernando Vieira Paulovich ; Filipe da Silva Lima ; Hugo van Ingen ; Ingrid Bernardes Santana Martins ; João Ruggiero Neto ; Jorge Chahine ; José Nelson Onuchic ; Juliana Sakamoto Yoneda ; Michele Cascella ; Peter Wolynes ; Ronaldo Júnio de Oliveira ; Sidney Jurado de Carvalho ; Susmita Roy
• Associated research grant(s): 25/03288-2 - Protein Electrostatics Conference, AR.EXT; 24/09560-3 - Probing the Energy Landscape of Intrinsically Disordered Proteins, AP.R SPRINT
• Associated scholarship(s): 25/05278-4 - Probing the mechanism of action of peptides with antimicrobial and anticancer potential on cell membranes, BP.DD; 24/21775-5 - Exploring the Folding Energy Landscape of Leptin: A Pierced Lasso Topology Protein, BP.IC; 24/23092-2 - Investigating the mechanism of action of the synthetic peptide E-MP1 on bacterial and cancer cell membrane models by Molecular Dynamics simulations at equilibrium and constant pH, BP.IC; + associated scholarships 24/23443-0 - Development of the Energy Landscape Visualization Method (ELViM): Limits, Parameterization and Optimization, BP.TT; 24/23378-3 - Characterization of IDPS in solution and lipid membrane/IDPs interaction, BP.DD; 24/10009-0 - MODULATION OF ANTIFUNGAL ACTIVITY: SYNERGISTIC EFFECT OF SOCIAL WASP PEPTIDES, POLYBIA-MPII AND POLYBIA-MPI, ON MIMETIC MEMBRANES, BP.IC; 24/10235-0 - Effect of Membrane Potential on the Adsorption of pH-Responsive Bioactive Peptides on Anionic Lipid Membranes, BP.IC; 24/09329-0 - Practices for the acquisition and data analysis of membrane/protein (IDPs) interaction using LUVs from small angle X-Ray scattering (SAXS) as model membranes, BP.TT; 24/09991-4 - Implementation of a Numerical Methodology for Integrating Data Obtained from Molecular Dynamics Simulations and SAXS/SANS in Biological Membranes, BP.TT; 21/15028-4 - Elucidating the functional plasticity of intrinsically disordered proteins by the study of energy landscape, BP.DR - associated scholarships

Abstract

A large fraction of the proteome of various organisms corresponds to polypeptides that do not form a defined three-dimensional structure. An entirely disordered polypeptide is known as an intrinsically disordered protein (IDP), and a segment of a protein that devoids a stable three-dimensional structure is called an intrinsically disordered region (IDR). It is increasingly recognized that IDRs are not simply passive disordered segments that connect well-folded domains, but they display biological functions themselves such as molecular recognition or entropic chains. IDPs and IDRs participate in a wide range of relevant cellular processes such as signal transduction pathways, RNA metabolism, and DNA packaging. However, the lack of a well-defined native structure leads to significant conceptual and methodological challenges in characterizing the structure or structural ensemble of IDPs and IDRs. Disordered proteins populate a diverse set of conformations with exceptional spatio-temporal heterogeneity and extraordinary conformational flexibility. For this reason, the elucidation of the functional mechanisms of IDPs and IDRs presupposes a full description of their structural dynamics. In this context, we propose to dissect the energy landscape of a series of biologically relevant IDPs and IDRs through an iterative approach that combines novel computational algorithms and established experimental techniques such as in-solution Small-angle X-ray scattering (SAXS), synchrotron radiation circular dichroism (SRCD) and heteronuclear multidimensional Nuclear Magnetic Resonance (NMR) spectroscopy. The computational component of this proposal relies on two methods (and associated open-source codes) developed by our groups. The Energy Landscape Visualization Method (ELViM) was conceived as a multidimensional scaling method for describing protein-folding ensembles with great potential for investigating molecular mechanisms. Because the method does not depend on reaction coordinates or native reference structures, it is well-suited to tackle IDPs and IDRs. In contrast, the Surface Assessment Via grid Evaluation (SuAVE) method accounts for the effect of curvature in the calculations of structural properties of chemical interfaces regardless of the chemical composition, symmetry, and level of atom coarseness. The proposed research will contribute to better describe the structural ensemble of molecules that do not have a stable well-characterized structure and that display broad conformational distributions. By doing so, the joint research group will work to decipher how protein plasticity modulates function, thus allowing us to infer key factors that trigger diseases such as Parkinson and diabetes Melittus, among others. The project will also contribute to the training of skilled individuals in the areas of computational biophysics and integrated structural biology, with emphasis on NMR, SRCD and SAXS. (AU)

Scientific publications

(5)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

PANTANO, SERGIO; CAPECE, LUCIANA; GAGLIARDI, LAURA; MERZ, KENNETH M.; BATISTA, VICTOR; SOARES, THEREZA A.. Computational Chemistry in the Global South: A Latin American Perspective. JOURNAL OF CHEMICAL THEORY AND COMPUTATION, v. 21, n. 4, p. 2-pg., 2025-02-25. (22/07231-7)

GRYN'OVA, GANNA; BEREAU, TRISTAN; MULLER, CAROLIN; FRIEDERICH, PASCAL; WADE, REBECCA C.; NUNES-ALVES, ARIANE; SOARES, THEREZA A.; MERZ JR, KENNETH. EDITORIAL: Chemical Compound Space Exploration by Multiscale High-Throughput Screening and Machine Learning. JOURNAL OF CHEMICAL INFORMATION AND MODELING, v. 64, n. 15, p. 2-pg., 2024-08-12. (22/07231-7)

VIEGAS, RAFAEL G.; MARTINS, INGRID B. S.; LEITE, VITOR B. P.. Understanding the Energy Landscape of Intrinsically Disordered Protein Ensembles. JOURNAL OF CHEMICAL INFORMATION AND MODELING, v. 64, n. 10, p. 9-pg., 2024-05-07. (23/02219-1, 22/07231-7)

PANTANO, SERGIO; CAPECE, LUCIANA; GAGLIARDI, LAURA; MERZ JR, KENNETH M.; BATISTA, VICTOR; SOARES, THEREZA A.. Computational Chemistry in the Global South: A Latin American Perspective. JOURNAL OF CHEMICAL INFORMATION AND MODELING, v. 65, n. 4, p. 2-pg., 2025-02-24. (22/07231-7)

DE OLIVEIRA, VINICIUS M.; MALOSPIRITO, CAIQUE C.; DA SILVA, FERNANDO B.; VIDEIRA, NATALIA B.; DIAS, MARIELI M. G.; SANCHES, MURILO N.; LEITE, VITOR B. P.; FIGUEIRA, ANA CAROLINA M.. Exploring the molecular pathways of the activation process in PPARγ recurrent bladder cancer mutants. Journal of Chemical Physics, v. 161, n. 16, p. 10-pg., 2024-10-28. (23/02219-1, 19/14465-1, 16/02348-2, 18/11614-3, 20/08366-8, 21/15028-4, 19/22540-3, 19/10274-7, 22/07231-7, 16/19766-1)