Rigid proteins and softening of biological membranes-with application to HIV-induced cell membrane softening.

Himani Agrawal,Liping Liu,Pradeep Sharma,Matthew Zelisko

doi:10.1038/srep25412

Himani Agrawal, Liping Liu + Show 2 more

Open Access

https://doi.org/10.1038/srep25412

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Abstract

A key step in the HIV-infection process is the fusion of the virion membrane with the target cell membrane and the concomitant transfer of the viral RNA. Experimental evidence suggests that the fusion is preceded by considerable elastic softening of the cell membranes due to the insertion of fusion peptide in the membrane. What are the mechanisms underpinning the elastic softening of the membrane upon peptide insertion? A broader question may be posed: insertion of rigid proteins in soft membranes ought to stiffen the membranes not soften them. However, experimental observations perplexingly appear to show that rigid proteins may either soften or harden membranes even though conventional wisdom only suggests stiffening. In this work, we argue that regarding proteins as merely non-specific rigid inclusions is flawed, and each protein has a unique mechanical signature dictated by its specific interfacial coupling to the surrounding membrane. Predicated on this hypothesis, we have carried out atomistic simulations to investigate peptide-membrane interactions. Together with a continuum model, we reconcile contrasting experimental data in the literature including the case of HIV-fusion peptide induced softening. We conclude that the structural rearrangements of the lipids around the inclusions cause the softening or stiffening of the biological membranes.

Highlights

Perplexing in the sense that both hardening and softening are observed when proteins or inclusions impregnate a soft membrane
Molecular dynamics simulations on HIV-1 fusion peptide and DMPC system
To better inform the development of a continuum model we performed all-atom molecular dynamics (MD) calculations to assess the changes in the elastic properties of a prototypical membrane due to the addition of HIV fusion peptide

Summary

Introduction

Perplexing in the sense that both hardening and softening are observed when proteins or inclusions (that are essentially rigid) impregnate a soft membrane. The FP23 interacts with the target cell membrane in a non-specific way causing thinning (Fig. 1) and, in turn, softening of the membrane which subsequently allows pore formation. Through this pore, HIV can release RNA into the target cell for replication[8]. We hypothesize that each protein (rigid as it may be) has a unique mechanical signature parametrized by its specific interfacial coupling to the surrounding membrane. Together with this hypothesis, all-atom molecular dynamics (MD) simulations, and a complementary continuum mechanics model, we attempt to address the questions raised in the preceding paragraphs

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Conclusion