Srinivasan, Sriraksha , ALVAREZ LORENZO, DANIEL, Peter, Arun T. John , Vanni, Stefano
No
J. Cell Biol.
Article
Científica
6.4
06/08/2024
001285029400001
This work develops a fast and easy-to-use protocol based on coarse-grained molecular dynamics simulations to characterize lipid binding to lipid transfer proteins (LTPs). The protocol displays accurate results on lipid binding pathways, identification of hydrophobic pockets and novel LTPs, as well as on lipid binding of multiple lipids to BLTPs. The characterization of lipid binding to lipid transfer proteins (LTPs) is fundamental to understand their molecular mechanism. However, several structures of LTPs, and notably those proposed to act as bridges between membranes, do not provide the precise location of their endogenous lipid ligands. To address this limitation, computational approaches are a powerful alternative methodology, but they are often limited by the high flexibility of lipid substrates. Here, we develop a protocol based on unbiased coarse-grain molecular dynamics simulations in which lipids placed away from the protein can spontaneously bind to LTPs. This approach accurately determines binding pockets in LTPs and provides a working hypothesis for the lipid entry pathway. We apply this approach to characterize lipid binding to bridge LTPs of the Vps13-Atg2 family, for which the lipid localization inside the protein is currently unknown. Overall, our work paves the way to determine binding pockets and entry pathways for several LTPs in an inexpensive, fast, and accurate manner.