α-Synuclein (α-syn) is an abundant neuronal protein associated with Parkinson’s disease that is disordered in solution, but exists in equilibrium between a bent- and an elongated-helix on negatively charged membranes. Here, neutron reflectometry (NR) and fluorescence spectroscopy were employed to uncover molecular details of the interaction between α-syn and two anionic lipids, phosphatidic acid (PA) and phosphatidylserine (PS). Both NR and site-specific Trp measurements indicate that penetration depth of α-syn is similar for either PA- or PS-containing membranes (~9–11 Å from bilayer center) even though there is a preference for α-syn binding to PA. However, closer examination of the individual Trp quenching profiles by brominated lipids reveal differences into local membrane interactions especially at position 39 where conformational heterogeneity was observed. The data also indicate that while W94 penetrates the bilayer as deeply as W4, W94 resides in a more polar surrounding. Taken together, we suggest the N- and C-terminal regions near positions 4 and 94 are anchored to the membrane, while the putative linker spanning residue 39 samples multiple conformations, which are sensitive to the chemical nature of the membrane surface. This flexibility may enable α-syn to bind diverse biomembranes in vivo.
important, as it may assist in designing channelrhodopsin variants with specific properties for optogenetics applications.To dissect structural elements that may act as gates and to explore how protein and water dynamics respond to changes in the protonation state, we combined extensive bioinformatics analyses with molecular dynamics simulations of channelrhodopsin and of bacteriorhodopsin mutants that model specific channelrhodopsin interactions, or have altered proton-transfer kinetics. In some of these mutants, we find that perturbation of specific hydrogen bonds is coupled to the rapid formation of water bridges that could assist proton transfer. In simulations on channelrhodopsin embedded in hydrated lipid membranes, the dynamics of water wires and hydrogen bonds inter-connecting remote regions of the protein are tightly coupled to the protonation state.
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