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Computational analysis of aspartic protease plasmepsin II complexed with EH58 inhibitor: a QM/MM MD study

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Abstract

Plasmepsin (PM) II is one of four enzymes in the food vacuole of Plasmodium falciparum. It has become an attractive target for combating malaria through research regarding its importance in the P. falciparum metabolism and life cycle, making it the target of choice for structure-based drug design. This paper reports the results of hybrid quantum mechanics / molecular mechanics (QM/MM) molecular dynamics (MD) simulations employed to study the details of the interactions established between PM II and N-(3–{(2-benzo[1, 3]dioxol-5-yl-ethyl)[3-(1-methyl-3-oxo-1,3-dihydro-isoindol-2-yl) propionyl]-amino}-1-benzyl-2-(hydroxyl-propyl)-4-benzyloxy-3,5dimethoxy-benzamide (EH58), a well-known potent inhibitor for this enzyme. Electrostatic binding free energy and energy terms decomposition have been computed for PM II complexed with the EH58 inhibitor. The results reveal that there is a strong interaction between Asp34, Val78, Ser79, Tyr192 and Asp214 residues and the EH58 inhibitor. In addition, we have computed the potential of the mean force (PMF) profile in order to assign the protonation state of the two catalytic aspartates in PM II-EH58 complex. The results indicate that the protonation of Asp214 favors a stable active site structure, which is consistent with our electrostatic binding free energy calculation and with previous published works.

Figure that most Structure of PM II-EH58 complex in cubic box, in especial the ligand and the catalytic residues.

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Acknowledgments

The authors would like to thank Conselho Nacional Científico e Tecnológico, Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior, Financiadora de Estudos e Projetos, Fundação de Amparo e Desenvolvimento da Pesquisa and Pró-Reitoria de Pesquisa e Pós-Graduação of Universidade Federal do Pará (Brazilian Agencies) for their financial support for this work.

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  1. Laboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, UFPA, Rua Augusto Corrêa, 01, Guamá CEP, 66075-110, Belém, PA, Brazil

    Natália de Farias Silva, Jerônimo Lameira & Cláudio Nahum Alves

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  1. Natália de Farias Silva
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  2. Jerônimo Lameira
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Correspondence to Cláudio Nahum Alves.

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ESM 1

Supplementary information is available regarding the potential energy derived from the standard QM/MM and comparative analysis of pKa values of the aspartate residues within the “cluster method” versus the empirical propKa program. Representation of the time evolution of the interaction energy between the protein-inhibitor complex obtained along AM1/MM molecular dynamics during the last 100 ps of the simulation to model A and B (DOC 363 kb)

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de Farias Silva, N., Lameira, J. & Alves, C.N. Computational analysis of aspartic protease plasmepsin II complexed with EH58 inhibitor: a QM/MM MD study. J Mol Model 17, 2631–2638 (2011). https://doi.org/10.1007/s00894-011-0963-1

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