Insights into lipid-protein interactions from computer simulations

Abstract

Lipid-protein interactions play an important direct role in the function of many membrane proteins. We argue they are key players in membrane structure, modulate membrane proteins in more subtle ways than direct binding, and are important for understanding the mechanism of classes of hydrophobic drugs. By directly comparing membrane proteins from different families in the same, complex lipid mixture, we found a unique lipid environment for every protein. Extending this work, we identified both differences and similarities in the lipid environment of GPCRs, dependent on which family they belong to and in some cases their conformational state, with particular emphasis on the distribution of cholesterol. More recently, we have been studying modes of coupling between protein conformation and local membrane properties using model proteins. In more applied approaches, we have used similar methods to investigate specific hypotheses on interactions of lipid and lipid-like molecules with ion channels. We conclude this perspective with some considerations for future work, including a new more sophisticated coarse-grained force field (Martini 3), an interactive visual exploration framework, and opportunities to improve sampling.

Studying KcsA Channel Clustering Using Single Channel Voltage-Clamp Fluorescence Imaging*

“…In the last years, the membrane curvature has moved into the focus of membrane protein research (Iversen et al, 2015;Tieleman et al, 2021), one prominent example being the exact arrangement of the ATPases in the tubular cristae of mitochondria (Blum et al, 2019) or the mechanosensitive FIGURE 5 | amplitude histogram is shown in e; in total 5 channels were present in the recording. (E), Current amplitude histograms of KcsA channels in pure POPE at room temperature (T~21 °C, top) and after heating up the system to 40 °C (bottom).…”

“…Piezo channels (Guo and MacKinnon, 2017). Also coarse-grained simulations of a voltage-gated ion channel, KvAP, suggest deformation of the surrounding membrane (Tieleman et al, 2021). It has been experimentally shown that the curvature leads to a sorting of KvAP channels according to the preferred curvature (Quemeneur et al, 2014).…”

Lipid-mediated organization of prestin in the outer hair cell membrane and its implications in sound amplification

“…[33][34][35][36][37][38][39] In order to improve sampling of lipid-protein interactions, especially in heterogeneous membranes, many MD studies have taken advantage of coarse-grained (CG) representations, e.g., using Martini, a widely used CG method for lipid structures. 40,41 Martini CG simulations of membranes and membrane proteins have contributed significantly to the understanding of how membrane proteins modulate their lipidic environments, both at the distribution and structural levels. 42,43 Here, we have employed an extensive set of MD simulations to characterize the structural effects of prestin on the membrane.…”

COGRIMEN: Coarse-Grained Method for Modeling of Membrane Proteins in Implicit Environments

“…In the COGRIMEN method, we employ the MARTINI 17 force field to represent coarse-grained proteins. MARTINI proved to be very effective in studying membrane behavior and lipid–protein interactions, 43 which can be even more accurate in refined MARTINI3. 44 In standard MARTINI, the hydrophobic effect is modeled by having stronger pairwise interactions between similar polar (P-type) and apolar (C-type) bead types compared to their cross interactions.…”