title: Unraveling the distinctive features of hemorrhagic and non-hemorrhagic snake venom metalloproteinases using molecular simulations.
abstract: Snake venom metalloproteinases are important toxins that play fundamental roles during envenomation. They share a structurally similar catalytic domain, but with diverse hemorrhagic capabilities. To understand the structural basis for this difference, we build and compare two dynamical models, one for the hemorrhagic atroxlysin-I from Bothrops atrox and the other for the non-hemorraghic leucurolysin-a from Bothrops leucurus. The analysis of the extended molecular dynamics simulations shows some changes in the local structure, flexibility and surface determinants that can contribute to explain the different hemorrhagic activity of the two enzymes. In agreement with previous results, the long Ω-loop (from residue 149 to 177) has a larger mobility in the hemorrhagic protein. In addition, we find some potentially-relevant differences at the base of the S1' pocket, what may be interesting for the structure-based design of new anti-venom agents. However, the sharpest differences in the computational models of atroxlysin-I and leucurolysin-a are observed in the surface electrostatic potential around the active site region, suggesting thus that the hemorrhagic versus non-hemorrhagic activity is probably determined by protein surface determinants.
authors.affiliation: Depto de Pesquisa e Desenvolvimento, Fundação Ezequiel Dias, Belo Horizonte, Minas Gerais, 3010-010, Brazil.
authors.forename: Raoni Almeida
authors.initials: RA
authors.lastname: de Souza
authors.affiliation: C/ Julián Clavería 8. Dpto. de Química Física y Analítica, Universidad de Oviedo, 33006, Oviedo, Asturias, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Díaz
authors.affiliation: Avenida Antônio Carlos 6627, Depto. de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil.
authors.forename: Ronaldo Alves Pinto
authors.initials: RA
authors.lastname: Nagem
authors.affiliation: Avenida Antônio Carlos 6627, Depto. de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil.
authors.forename: Rafaela Salgado
authors.initials: RS
authors.lastname: Ferreira
authors.affiliation: C/ Julián Clavería 8. Dpto. de Química Física y Analítica, Universidad de Oviedo, 33006, Oviedo, Asturias, Spain. dimas@uniovi.es.
authors.forename: Dimas
authors.initials: D
authors.lastname: Suárez
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017837:Bothrops / Q000378:metabolism; D020134:Catalytic Domain; D003435:Crotalid Venoms / Q000737:chemistry*; D008666:Metalloendopeptidases / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D055672:Static Electricity; D015032:Zinc / Q000737:chemistry
chemical_list: D003435:Crotalid Venoms; D008666:Metalloendopeptidases; C069317:hemorrhagic metalloproteinase; D015032:Zinc
keywords: Homology modeling; Metalloproteinases; Molecular dynamics simulations; Molecular recognition; Venom toxins