Developing computational methods to determine the thermodynamics of lipid phase coexistence

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Project Description Recent years have brought a new appreciation for the role of phase separation in biology, and in particular phase coexistence in the lipid membranes that define the boundaries in and around our cells. Studying this phenomenon using molecular simulation methods remains challenging because of the time- and length-scales involved, and while coarse-grained simulations have reproduced the existence of phase coexistence, to date there are no methods for determining the thermodynamics governing the process. We will develop a new method that will fill this gap, built around the weighted ensemble simulation technique using a contact-based collective variable. We will implement and test a protocol for measuring the free energy to demix 3- component membranes, using coarse-grained simulation with the MARTINI force field as our test suite. In addition, we will implement and validate a new method to couple weighted ensemble with temperature replica exchange, as a way to further speed statistical convergence of the calculations. Finally, we will extend the method to handle the partitioning and aggregation of surface-bound peptides between coexisting phases, using the antifungal lipopeptide fengycin as a test case.