Cardiolipin mediates dynamic receptor-channel interactions within the mitochondrial TIM23 protein import complex.

Using a combination of coarse-grained and atomistic molecular dynamics simulations we have investigated the membrane binding and folding properties of the membrane lytic peptide of Flock House virus (FHV). FHV is an animal virus and an excellent model system for studying cell entry mechanisms in non-enveloped viruses. FHV undergoes a maturation event where the 44 C-terminal amino acids are cleaved from the major capsid protein, forming the membrane lytic (γ) peptides. Under acidic conditions, γ is released from the capsid interior allowing the peptides to bind and disrupt membranes. The first 21 N-terminal residues of γ, termed γ1, have been resolved in the FHV capsid structure and γ1 has been the subject of in vitro studies. γ1 is structurally dynamic as it adopts helical secondary structure inside the capsid and on membranes, but it is disordered in solution. In vitro studies have shown the binding free energies to POPC or POPG membranes are nearly equivalent, but binding to POPC is enthalpically driven, while POPG binding is entropically driven. Through coarse-grained and multiple microsecond all-atom simulations the membrane binding and folding properties of γ1 are investigated against homogeneous and heterogeneous bilayers to elucidate the dependence of the microenvironment on the structural properties of γ1. Our studies provide a rationale for the thermodynamic data and suggest binding of γ1 to POPG bilayers occurs in a disordered state, but γ1 must adopt a helical conformation when binding POPC bilayers.

The PACE force field presents an attractive model for conducting molecular dynamics simulations of membrane-protein systems. PACE is a hybrid model, in which lipids and solvents are coarse-grained consistent with the MARTINI mapping, while proteins are described by a united-atom model. However, given PACE is linked to MARTINI, which is widely used to study membranes, the behavior of proteins interacting with membranes has only been limitedly examined in PACE. In this study PACE is employed to examine the behavior of several peptides in membrane environments, namely WALP peptides, melittin and influenza hemagglutinin fusion peptide (HAfp). Overall, we find PACE provides an improvement over MARTINI for modeling helical peptides, based upon the membrane insertion energetics for WALP16 and more realistic melittin pore dynamics. Our studies on HAfp, which forms a helical hairpin structure, do not show the hairpin structure to be stable, which may point toward a deficiency in the model.

Lipidated proteins are an emerging class of hybrid biomaterials that can integrate the functional capabilities of proteins into precisely engineered nano-biomaterials with potential applications in biotechnology, nanoscience, and biomedical engineering. For instance, fatty-acid-modified elastin-like polypeptides (FAMEs) combine the hierarchical assembly of lipids with the thermoresponsive character of elastin-like polypeptides (ELPs) to form nanocarriers with emergent temperature-dependent structural (shape or size) characteristics. Here, we report the biophysical underpinnings of thermoresponsive behavior of FAMEs using computational nanoscopy, spectroscopy, scattering, and microscopy. This integrated approach revealed that temperature and molecular syntax alter the structure, contact, and hydration of lipid, lipidation site, and protein, aligning with the changes in the nanomorphology of FAMEs. These findings enable a better understanding of the biophysical consequence of lipidation in biology and the rational design of the biomaterials and therapeutics that rival the exquisite hierarchy and capabilities of biological systems.

Flock House virus (FHV) is a well-characterized model system to study infection mechanisms in non-enveloped viruses. A key stage of the infection cycle is the disruption of the endosomal membrane by a component of the FHV capsid, the membrane active γ peptide. In this study, we perform all-atom molecular dynamics simulations of the 21 N-terminal residues of the γ peptide interacting with membranes of differing compositions. We carry out umbrella sampling calculations to study the folding of the peptide to a helical state in homogenous and heterogeneous membranes consisting of neutral and anionic lipids. From the trajectory data, we evaluate folding energetics and dissect the mechanism of folding in the different membrane environments. We conclude the study by analyzing the extent of configurational sampling by performing time-lagged independent component analysis.

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