A joint reaction coordinate for computing the free energy landscape of pore nucleation and pore expansion in lipid membranes

Abstract

Topological transitions of membranes, such as pore formation or membrane fusion, play key roles in biology, biotechnology, and in medical applications. Calculating the related free energy landscapes has been complicated by the fact that such processes involve a sequence of transitions along highly distinct directions in conformational space, making it difficult to define good reaction coordinates (RCs) for the overall process. In this study, we present a new RC capable of driving both pore nucleation and pore expansion in lipid membranes. The potential of mean force (PMF) along the RC computed with molecular dynamics (MD) simulations provides a comprehensive view on the free-energy landscape of pore formation, including a barrier for pore nucleation, the size, free energy, and metastability of the open pore, and the energetic cost for further pore expansion against the line tension of the pore rim. We illustrate the RC by quantifying the effects (i) of simulation system size and (ii) of the addition of dimethyl sulfoxide (DMSO) on the free energy landscape of pore formation. PMF calculations along the RC provide mechanistic and energetic understanding of pore formation, hence they will be useful to rationalize the effects of membrane-active peptides, electric fields, and membrane composition on transmembrane pores.Graphical TOC Entry

Sequential Water and Headgroup Merger: Membrane Poration Paths and Energetics from MD Simulations

“…A previous study also reported that for 20 independent, unbiased simulations of DMPC pores, zero closed within 500 ns ( 17 ), which suggests that the closure barrier is substantial. The energy landscape suggests that applied surface tension should increase the radius of this metastable defect, in accordance with a Litster type energy model, as has been reported in other studies ( 13 , 49 ).…”

“…This value has not been reported previously because the full PMF, including the entire metastable basin, was not resolved with a single RC. Just recently, however, this result has been confirmed, independently ( 49 ), using an empirical RC that combines the slab scheme of ( 14 ) with a lateral expansion RC. A previous study also reported that for 20 independent, unbiased simulations of DMPC pores, zero closed within 500 ns ( 17 ), which suggests that the closure barrier is substantial.…”