Cofilin‐Membrane Interactions: Electrostatic Effects in Phosphoinositide Lipid Binding

Abstract

The actin cytoskeleton interacts with the cell membrane primarily through the indirect interactions of actin-binding proteins such as cofilin-1. The molecular mechanisms underlying the specific interactions of cofilin-1 with membrane lipids are still unclear. Here, we performed coarse-grain molecular dynamics simulations of cofilin-1 with complex lipid bilayers to analyze the specificity of protein-lipid interactions. We observed the maximal interactions with phosphoinositide (PIP) lipids, especially PIP 2 and PIP 3 lipids. A good match was observed between the residues predicted to interact and previous experimental studies. The clustering of PIP lipids around the membrane bound protein leads to an overall lipid demixing and gives rise to persistent membrane curvature. Further, through a series of control simulations, we observe that both electrostatics and geometry are critical for specificity of lipid binding. Our current study is a step towards understanding the physico-chemical basis of cofilin-PIP lipid interactions.

Palmitoylation of the Glucagon-like Peptide-1 Receptor Modulates Cholesterol Interactions at the Receptor–Lipid Microenvironment

“…94 In addition, the specificity of lipid interactions such as with different types of charged lipids has been previously shown with the Martini coarse-grain force field. 95 GPCRcholesterol interactions, in particular, have been characterized in detail by several coarse-grain simulation studies. 23,[25][26][27]29,31,32,96 Approaches to estimate GPCR-cholesterol energetics have been proposed 28,97,98 and have been shown to not be very strong, in line with the high dynamics observed in this study.…”

“…Lipid chain modifications in a number of membrane-embedded and membrane-bound proteins have been studied by coarse-grain simulations such as caveolin-1 , and H-Ras, and transmembrane proteins such as CD44 . In addition, the specificity of lipid interactions such as with different types of charged lipids has been previously shown with the Martini coarse-grain force field . GPCR-cholesterol interactions, in particular, have been characterized in detail by several coarse-grain simulation studies. ,− ,,,, Approaches to estimate GPCR-cholesterol energetics have been proposed ,, and have been shown to not be very strong, in line with the high dynamics observed in this study.…”

Phafins Are More Than Phosphoinositide-Binding Proteins

“…In addition to electrostatic interactions, hydrophobic amino acid residues located near the basic patch contribute to lipid ligation. Membrane anchoring is also augmented by additional mechanisms including hydrophobic insertion, protonation of a histidine switch, and coincidence detection [52][53][54][55].…”

Improved Protein Dynamics and Hydration in the Martini3 Coarse-Grain Model

“…The Martini2 version of the force-field included the first extensively tested protein parameters and was shown to accurately model membrane–protein dynamics ,− and has been validated against atomistic simulations. , To model the secondary structural elements accurately, specific bonded parameters were used, but the standard Martini2 model did not include tertiary structural constraints. In fact, this was important to model interdomain dynamics such as in channel function .…”