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1/ My paper on discovering the #ReactionCoordinate & characterizing the rate-limiting step for passive #LipidTransport is out now in @JPhysChem B!
https://pubs.acs.org/doi/full/10.1021/acs.jpcb.0c04139
A summary of our findings and their significance:
https://pubs.acs.org/doi/full/10.1021/acs.jpcb.0c04139
A summary of our findings and their significance:
2/ Maintaining heterogeneous membrane compositions is key to biological function. Perhaps the simplest way this could occur is through passive exchange of individual lipids between two membranes.
3/ Partially due to inconsistencies between experiments and previous #MDsimulations, a molecular understanding of the rate-limiting step of passive #LipidTransport has remained elusive until now.
4/ #MDsimulations are great for exploring microscopic dynamics. But, quantifying the free energy (FE) barrier associated with the rate-limiting step requires knowledge of the #ReactionCoordinate.
5/ If the FE is computed in terms of an order parameter that is not the #ReactionCoordinate, the activation barrier is often underestimated. (For further discussion of this issue, check out Dan Zuckerman’s blog post and references therein. http://statisticalbiophysicsblog.org/?p=160 )
6/ We resolve the discrepancy between experimental and previous computational findings by identifying the #ReactionCoordinate for passive lipid exchange. To do so, we harvest over 1000 trajectories of lipid insertion using all-atom and #CG_Martini models.
7/ We find that lipid insertion exhibits barrier crossing dynamics, which is consistent with experiments! (Be sure to check out the SI movies if you want to see these dynamics)
8/ We analyze over 50 order parameters for their potential to be the #ReactionCoordinate using committor analysis.
9/ We find that the #ReactionCoordinate monitors the formation and breakage of hydrophobic contacts between the exchanging lipid and membrane. Consistent with experiments, FE profiles as a function of the #ReactionCoordinate exhibit a significant barrier for lipid insertion.
10/ The lipid’s displacement from the membrane in z, which has traditionally been used to monitor lipid insertion, is not the reaction coordinate and does not resolve the FE barrier for insertion.
11/ Using knowledge of the #ReactionCoordinate, we formulate an expression for the lipid exchange rate to compare to experimental values. While we resolve qualitative discrepancies with experiment, quantitative discrepancies persist, and we discuss potential reasons for this.
12/ By identifying the #ReactionCoordinate for passive lipid exchange, we discover that the breakage of hydrophobic contacts limits the rate of passive lipid transport and that the formation of hydrophobic contacts gives rise to a FE barrier for lipid insertion.
13/ The barrier for insertion likely plays an important biological role since it helps ensure that membrane compositions, which are spatiotemporally regulated to maintain cell homeostasis, are not easily disrupted.
14/ We suspect that the formation & breakage of hydrophobic contacts may generally give rise to a FE barrier for transporting amphiphiles, including synthetic surfactants and lipopeptides, which is not resolved by measuring the amphipile’s displacement from a membrane in z.
15/ (Consistent with this idea, Lin & @agrossfield found that a hydrophobic contact order parameter was necessary to characterize lipopeptide insertion from a micelle into a lipid bilayer, whereas the displacement in z was insufficient. https://www.cell.com/biophysj/fulltext/S0006-3495(15)00717-1)
16/ Knowledge of the #ReactionCoordinate for passive #LipidTransport provides a foundation to understand how catalysts of lipid exchange work: Lipid transfer proteins may efficiently extract lipids by lowering the activation barrier for hydrophobic contact breakage.
17/ Catalysts of vesicle fusion may also promote the breakage and formation of hydrophobic contacts. (For ex, Larsson & @kassonlab have shown that viral fusion peptides promote hydrophobic lipid tail protrusions and contacts https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1002950)
18/18 Therefore, common physical properties of lipids, specifically their hydrophobicity, may be exploited to control both non-vesicular and vesicular #LipidTransport between cell membranes.
