02392nas a2200229 4500008004100000022001400041245015700055210006900212260000800281300001000289490000800299520155700307653002901864653002101893653003101914653000901945100002401954700002101978700001701999700001602016856013002032 2019 eng d a0009-308400aLipid composition and salt concentration as regulatory factors of the anion selectivity of VDAC studied by coarse-grained molecular dynamics simulations0 aLipid composition and salt concentration as regulatory factors o cMAY a66-760 v2203 a

The voltage-dependent anion channel (VDAC) is a mitochondrial outer membrane protein whose fundamental function is to facilitate and regulate the flow of metabolites between the cytosol and the mitochondrial inter membrane space. Using coarse-grained molecular dynamics simulations, we investigated the dependence of VDAC selectivity towards small inorganic anions on two factors: the ionic strength and the lipid composition. In agreement with experimental data we found that VDAC becomes less anion selective with increasing salt concentration due to the screening of a few basic residues that point into the pore lumen. The molecular dynamics simulations provide insight into the regulation mechanism of VDAC selectivity by the composition in the lipid membrane and suggest that the ion distribution is differently modulated by POPE compared to the POPC bilayer. This occurs through the more persistent interactions of acidic residues located at both rims of the beta-barrel with head groups of POPE which in turn impact the electrostatic potential and thereby the selectivity of the pore. This mechanism occurs not only in POPE single component membranes but also in a mixed POPE/POPC bilayer by an enrichment of POPE over POPC lipids on the surface of VDAC. Thus we show here that computationally-in-expensive coarse-grained simulations are able to capture, in a semi-quantitative way, essential features of VDAC anion selectivity and could pave the way toward a molecular level understanding of metabolite transport in natural membranes.

10aCoarse-grained molecular10aMembrane channel10aProtein-lipid interactions10aVDAC1 aVan Liefferinge, F.1 aKrammer, E., -M.1 aSengupta, D.1 aPrevost, M. uhttps://library.ncl.res.in/content/lipid-composition-and-salt-concentration-regulatory-factors-anion-selectivity-vdac-studied02523nas a2200205 4500008004100000022001400041245007500055210006900130260000800199300001200207490000800219520183200227653002702059653002302086653003102109100002002140700002702160700002002187856011002207 2022 eng d a0022-263100aMolecular mechanisms underlying caveolin-1 mediated membrane curvature0 aMolecular mechanisms underlying caveolin1 mediated membrane curv cJUN a225-2360 v2553 a

Caveolin-1 is one of the main protein components of caveolae that acts as a mechanosensor at the cell membrane. The interactions of caveolin-1 with membranes have been shown to lead to complex effects such as curvature and the clustering of specific lipids. Here, we review the emerging concepts on the molecular interactions of caveolin-1, with a focus on insights from coarse-grain molecular dynamics simulations. Consensus structural models of caveolin-1 report a helix-turn-helix core motif with flanking domains of higher disorder that could be membrane composition dependent. Caveolin-1 appears to be mainly surface-bound and does not embed very deep in the membrane to which it is bound. The most interesting aspect of caveolin-1 membrane binding is the interplay of cholesterol clustering and membrane curvature. Although cholesterol has been reported to cluster in the vicinity of caveolin-1 by several approaches, simulations show that the clustering is maximal in membrane leaflet opposing the surface-bound caveolin-1. The intrinsic negative curvature of cholesterol appears to stabilize the negative curvature in the opposing leaflet. In fact, the simulations show that blocking cholesterol clustering (through artificial position restraints) blocks membrane curvature, and vice versa. Concomitant with cholesterol clustering is sphingomyelin clustering, again in the opposing leaflet, but in a concentration-dependent manner. The differential stress due to caveolin-1 binding and the inherent asymmetry of the membrane leaflets could be the determinant for membrane curvature and needs to be further probed. The review is an important step to reconcile the molecular level details emerging from simulations with the mesoscopic details provided by state of the art experimental approaches. [GRAPHICS] .

10aCholesterol clustering10aMembrane curvature10aProtein-lipid interactions1 aPrakash, Shikha1 aMalshikare, Hrushikesh1 aSengupta, Durba uhttps://library.ncl.res.in/content/molecular-mechanisms-underlying-caveolin-1-mediated-membrane-curvature01829nas a2200217 4500008004100000022001400041245009100055210006900146260000900215490000700224520105300231653002101284653002101305653003701326653003501363653003101398100002001429700002001449700002001469856012201489 2023 eng d a1439-423500aCofilin-membrane interactions: electrostatic effects in phosphoinositide lipid binding0 aCofilinmembrane interactions electrostatic effects in phosphoino cFEB 0 v243 a

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 PIP2 and PIP3 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.

10acomplex membrane10alipid clustering10aMartini coarse-grain simulations10aMolecular dynamics simulations10aProtein-lipid interactions1 aPrakash, Shikha1 aKrishna, Anjali1 aSengupta, Durba uhttps://library.ncl.res.in/content/cofilin-membrane-interactions-electrostatic-effects-phosphoinositide-lipid-binding