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Unraveling the distinctive features of hemorrhagic and non-hemorrhagic snake venom metalloproteinases using molecular simulations

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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.

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Acknowledgments

This research was partially supported by the GRUPIN14-049 (FICyT, Spain) Grant and by the Brazilian Grants CAPES PVE 118/2013 and CAPES PDSE 4165/14-4.

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Authors and Affiliations

  1. Depto de Pesquisa e Desenvolvimento, Fundação Ezequiel Dias, Belo Horizonte, Minas Gerais, 3010-010, Brazil

    Raoni Almeida de Souza

  2. C/ Julián Clavería 8. Dpto. de Química Física y Analítica, Universidad de Oviedo, 33006, Oviedo, Asturias, Spain

    Natalia Díaz & Dimas Suárez

  3. Avenida Antônio Carlos 6627, Depto. de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil

    Ronaldo Alves Pinto Nagem & Rafaela Salgado Ferreira

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  1. Raoni Almeida de Souza
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  2. Natalia Díaz
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  3. Ronaldo Alves Pinto Nagem
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  4. Rafaela Salgado Ferreira
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Correspondence to Dimas Suárez.

Electronic supplementary material

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10822_2015_9889_MOESM1_ESM.docx

SCC-DFTB/AMBER optimized inter-atomic distances for the zinc site in the 4Q1L structure (Table S1). View of the B3LYP/6-31G(d) PCM cluster model of the Zn1 site (Fig. S1). Force field parameters for the Zn1···ligand interactions. Sequence alignment of the templates used in atroxlysin-I model production (Fig. S2). Evaluation of the atroxlysin-I model produced by Prosa II sever (Fig S3).Computed pK a values (Table S2). Details of Ca2+···ligand interactions during the MD simulations (Table S3). Time evolution of RMSDs (Figs S4-S5). Superposition of the MD-averaged structures (Fig. S6). Structural alignment of the templates used in atroxlysin-I model production (Fig. S7). (DOCX 4441 kb)

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de Souza, R.A., Díaz, N., Nagem, R.A.P. et al. Unraveling the distinctive features of hemorrhagic and non-hemorrhagic snake venom metalloproteinases using molecular simulations. J Comput Aided Mol Des 30, 69–83 (2016). https://doi.org/10.1007/s10822-015-9889-5

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