Computational studies of membrane pore formation induced by Pin2

Abstract

Understanding, at the molecular level, the effect of AMPs on biological membranes is of crucial importance given the increasing number of multidrug-resistant bacteria. Being part of an ancient type of innate immunity system, AMPs have emerged as a potential solution for which bacteria have not developed resistance. Traditional antibiotics specifically act on biosynthetic pathways, while AMPs may directly destabilize the lipid membrane, but it is unclear how AMPs affect the membrane’s stability. We performed multiscale molecular dynamics simulations to investigate the structural features leading to membrane pores formation on zwitterionic and anionic membranes by the antimicrobial peptide (AMP) Pandinin 2 (Pin2). Some experimental reports propose that Pin2 could form barrel-stave pores, while others suggest that it could form toroidal pores. Since there is no conclusive evidence of which type of pore is formed by Pin2 on bilayers, performing molecular dynamics simulations on these systems could shed some light on whether or not or what type of pore Pin2 forms on model membranes. Our results are focused on a detailed description of the pore formation by Pin2 in POPC and POPE:POPG membranes., which strongly suggest that Pin2 forms a toroidal pore and not a barrel-shaped pore; this type of pore also affects the membrane properties. In the process, a phospholipid remodeling in the POPE:POPG membrane takes place. Moreover, the pores formed by Pin2 indicate that they are selective for the chlorine ion. There are no previous ion selectivity reports for other AMPs with similar physicochemical properties, such as melittin and magainin.

Communicated by Ramaswamy H. Sarma

Keywords:

• Scorpion derived-peptides
• antimicrobial peptides
• molecular dynamics
• pore formation

Acknowledgements

We acknowledge Dirección General de Cómputo y de Tecnologías de Información y Comunicación, UNAM, for computer time at MIZTLI supercomputer. J.L V-B. was a doctoral student from Programa de Maestría y Doctorado en Ciencias Bioquímicas, Universidad Nacional Autónoma de México (UNAM) and received fellowship 445924/270480 from CONACYT.

Disclosure statement

The authors declare no competing financial interest.

Additional information

Funding

This work was supported by Programa UNAM-DGAPA-PAPIIT Grants IN221913 and IN108816, and by LANCAD-UNAM-DGTIC-033.