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rd 23 Congress of the International Union for Biochemistry and Molecular Biology th 44 Annual Meeting of the Brazilian Society for Biochemistry and Molecular Biology th th Foz do Iguaçu, PR, Brazil, August 24 to 28 , 2015 Conformational changes governing dengue virus capsid protein function and its inhibition by pep14-23 André F. Faustino1, Gabriela M. Guerra1, Roland G. Huber2, Axel Hollmann1, Marco M. Domingues1, Glauce M. Barbosa3, Francisco J. Enguita1, Peter J. Bond2, Miguel Castanho1, Andrea T. Da Poian3, Fabio C.L. Almeida3, Ivo C. Martins1, Nuno C. Santos1 1. Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal; 2. Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore; 3 – Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil. Introduction: Dengue virus (DENV) infection affects millions of people and is becoming a major global disease for which there is no specific available treatment. pep14-23 is a recently designed peptide, based on a conserved segment of DENV capsid (C) protein. It inhibits the interaction of DENV C with host intracellular lipid droplets (LDs), crucial for viral replication, as well as with VLDL [Carvalho et al. (2012) J. Virol. 86:2096; Martins et al. (2012) Biochem. J. 444:405; Faustino et al. (2014) Nanomedicine 10:247]. Objectives: Here we analyzed pep14-23 structure and ability to bind different phospholipids, relating the information obtained with the full-length DENV C structure and biological activity. Materials and Methods: Bioinformatics approaches were combined with biophysical methods such as circular dichroism, tensiometry, NMR and zeta potential measurements [Faustino et al. (2015) ACS Chem. Biol. 10:517]. Results and Discussion: We show that pep14-23 acquires α-helical conformation upon binding to negatively-charged phospholipid membranes, displaying an asymmetric charge distribution structural arrangement. Structure prediction for the N-terminal segment reveals four viable homodimer orientations that alternatively shield or expose the DENV C hydrophobic pocket. Taken together, these findings suggest a new biological role for the disordered N-terminal region, which may function as an autoinhibitory domain mediating DENV C interaction with its biological targets. Conclusions: The results fit with our current understanding of DENV C and pep14-23 structure and function, paving the way for similar approaches to understanding disordered proteins and improved peptidomimetics drug development strategies against DENV and related Flavivirus infections [Faustino et al. (2015) ACS Chem. Biol. 10:517; Faustino et al. (2015) Sci. Rep., in press]. Acknowledgements: Horizon 2020 – RISE (European Union), FCT-MEC (Portugal), CNPq and FAPERJ (Brazil). Keywords: Dengue virus; biophysics; bioinformatics. Brazilian Society for Biochemistry and Molecular Biology (SBBq)