Journal of Molecular Modeling

, 25:281 | Cite as

Antimicrobial peptide ROAD–1 triggers phase change in local membrane environment to execute its activity

  • Sheeja V. VasudevanEmail author
  • Ashutosh Kumar
Original Paper


Emergence of antibiotic-resistant pathogens has paved way for development of newer class of drugs that would not be susceptible to resistance. Antimicrobial peptides such as defensins that target the microbial membrane are promising candidates. ROAD–1 is an alpha-defensin present in the oral cavity of rhesus macaque and shares very high sequence similarity to human enteric defensin 5. In this study we have performed microsecond long all atom molecular dynamic simulations to understand the mechanism of action of ROAD–1. We find that ROAD–1 is able to adopt an energetically stable conformation predominantly stabilized by electrostatic interactions only in presence of bacterial membranes. In mammalian membrane even though it gets absorbed onto the bilayer, it is unable to adopt an equilibrium conformation. Binding of ROAD–1 to bilayer induces clustering of POPG molecules up to 15 Å around the peptide. POPG molecules show higher order parameters than the neighboring POPE implying coexistence of different phases. Analysis of binding free energy of ROAD–1–membrane complex indicates Arg1, Arg2, Arg7, and Arg25 to play key role in its antimicrobial activity. Unlike its homolog HD5, ROAD–1 is not observed to form a dimer. Our study gives insight into the membrane-bound conformation of ROAD–1 and its mechanism of action that can aid in designing defensin-based therapeutics.

Graphical abstract

Antimicrobial peptide ROAD–1 adopts a different membrane-bound conformation as compared with HD5 even though they belong to the same family implying a different mechanism of action.


Molecular dynamics simulation Electrostatic interaction Binding energy Antibiotic resistance Defensins 



SV would like to thank Department of Science and Technology, Govt. of India, for financial assistance (grant number SR/WOS-A/LS-566/2013) and C-DAC national supercomputing facilities for computational support. We would like to acknowledge Prof. P. V. Balaji, IIT Bombay for his valuable comments and computational support. SV would like to thank Nitin Kachariya and Rajalakshmi Panigrahi for assistance in making figures. SV would like to thank Prof. Micheal Selsted and Prof. Melaine Cocco for initiation into the world of antimicrobial peptides.

Compliance with ethical standards

Conflict of interest

The authors declare that they no conflict of interests.

Supplementary material

894_2019_4163_MOESM1_ESM.docx (41.9 mb)
ESM 1 (DOCX 42879 kb)


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© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Biosciences and BioengineeringIndian Institute of Technology BombayMumbaiIndia

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