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In this chapter, we discuss the analysis of membrane remodeling by proteins, pep- tides and nanoparticles using multi-scale computational methods; these include mainly molecular dynamics simulations at atomistic and coarse-grained levels, al- though we will also touch upon continuum mechanics models. The discussions will cover several systems that we have analyzed in recent studies, which include Sar1, the ESCRTIII complex, complexin and peptides from SARS-COVID-2; as comparison, we also briefly discuss the impact of polyelectrolyte coacervates and functionalized nanoparticles on membrane properties, including generation of membrane curvature and potential disruption of liposomes. These examples illustrate different molecular properties and mechanisms that are potentially relevant to membrane remodeling at different length scales. The results highlight both the values and limitations of different computational models for the analysis of membrane remodeling, thus underscoring the importance of integrating different computational approaches to cross-validate the results. 

The backbone hydrogen bonds of a peptide assembly derived from FUS-LC gain excess stability at the anionic membrane-water and air–water interfaces due to distinctive interfacial solvation properties. 

Abstract Synaptotagmin (syt) 1, a Ca²⁺sensor for synaptic vesicle exocytosis, functions in vivo as a multimer. Syt1 senses Ca²⁺via tandem C2-domains that are connected to a single transmembrane domain via a juxtamembrane linker. Here, we show that this linker segment harbors a lysine-rich, intrinsically disordered region that is necessary and sufficient to mediate liquid-liquid phase separation (LLPS). Interestingly, condensate formation negatively regulates the Ca²⁺-sensitivity of syt1. Moreover, Ca²⁺and anionic phospholipids facilitate the observed phase separation, and increases in [Ca²⁺]_ipromote the fusion of syt1 droplets in living cells. Together, these observations suggest a condensate-mediated feedback loop that serves to fine-tune the ability of syt1 to trigger release, via alterations in Ca²⁺binding activity and potentially through the impact of LLPS on membrane curvature during fusion reactions. In summary, the juxtamembrane linker of syt1 emerges as a regulator of syt1 function by driving self-association via LLPS. 

Many intrinsically disordered peptides have been shown to undergo liquid–liquid phase separation and form complex coacervates, which play various regulatory roles in the cell. Recent experimental studies found that such phase separation processes may also occur at the lipid membrane surface and help organize biomolecules during signaling events; in some cases, phase separation of proteins at the membrane surface was also observed to lead to significant remodeling of the membrane morphology. The molecular mechanisms that govern the interactions between complex coacervates and lipid membranes and the impacts of such interactions on their structure and morphology, however, remain unclear. Here we study the coacervation of poly-glutamate (E 30 ) and poly-lysine (K 30 ) in the presence of lipid bilayers of different compositions. We carry out explicit-solvent coarse-grained molecular dynamics simulations by using the MARTINI (v3.0) force-field. We find that more than 20% anionic lipids are required for the coacervate to form stable contact with the bilayer. Upon wetting, the coacervate induces negative curvature to the bilayer and facilitates local lipid demixing, without any peptide insertion. The magnitude of negative curvature, extent of lipid demixing, and asphericity of the coacervate increase with the concentration of anionic lipids. Overall, we observe a decrease in the number of contacts among the polyelectrolytes as the droplet spreads over the bilayer. Therefore, unlike previous suggestions, interactions among polyelectrolytes do not constitute a driving force for the membrane bending upon wetting by the coacervate. Rather, analysis of interaction energy components suggests that bending of the membrane is favored by enhanced interactions between polyelectrolytes with lipids as well as with counterions. Kinetic studies reveal that, at the studied polyelectrolyte concentrations, the coacervate formation precedes bilayer wetting.