Modeling of macromolecular structures and interactions represents an important challenge for computational biology, involving different time and length scales. However, this task can be facilitated through the use of coarse-grained (CG) models, which reduce the number of degrees of freedom and allow efficient exploration of complex conformational spaces. This article presents a new CG protein model named SIRAH, developed to work with explicit solvent and to capture sequence, temperature, and ionic strength effects in a topologically unbiased manner. SIRAH is implemented in GROMACS, and interactions are calculated using a standard pairwise Hamiltonian for classical molecular dynamics simulations. We present a set of simulations that test the capability of SIRAH to produce a qualitatively correct solvation on different amino acids, hydrophilic/hydrophobic interactions, and long-range electrostatic recognition leading to spontaneous association of unstructured peptides and stable structures of single polypeptides and protein-protein complexes.

Unsaturated and saturated phospholipids tend to laterally segregate, especially in the presence of cholesterol. Small molecules such as neurotransmitters, toxins, drugs etc. possibly modulate this lateral segregation. The small aromatic neurotransmitter serotonin (5-HT) has been found to bind to membranes. We studied the lipid structure and packing of a ternary membrane mixture consisting of palmitoyl-oleoylphosphatidylcholine, palmitoyl-sphingomyelin, and cholesterol at a molar ratio of 4/4/2 in the absence and in the presence of 5-HT, using a combination of solid-state 2 H NMR, atomic force microscopy, and atomistic molecular dynamics (MD) simulations. Both NMR and MD report formation of a liquid ordered (L o) and a liquid disordered (L d) phase coexistence with small domains. Lipid exchange between the domains was fast such that single component 2 H NMR spectra are detected over a wide temperature range. A drastic restructuring of the domains was induced when 5-HT is added to the membranes at a 9 mol% concentration relative to the lipids. 2 H NMR spectra of all components of the mixture showed two prominent contributions indicative of molecules of the same kind residing both in the disordered and the ordered phase. Compared to the data in the absence of 5-HT, the lipid chain order in the disordered phase was further decreased in the presence of 5-HT. Likewise, addition of serotonin increased lipid chain order within the ordered phase. These characteristic lipid chain order changes were confirmed by MD simulations. The 5-HTinduced larger difference in lipid chain order results in more pronounced differences in the hydrophobic thickness of the individual membrane domains. The correspondingly enlarged hydrophobic mismatch between ordered and disordered phases is assumed to increase the line tension at the domain boundary, which drives the system into formation of larger size domains. These results not only demonstrate that small membrane binding molecules such as neurotransmitters have a profound impact on essential membrane properties. It also suggests a mechanism by which the interaction of small molecules with membranes can influence the function of membrane proteins and non-cognate receptors. Altered membrane properties may modify lateral sorting of membrane protein, membrane protein conformation, and thus influence their function as suspected for neurotransmitters, local anesthetics, and other small drug molecules.

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Detailed knowledge on the formation of biomembrane domains, their structure, composition, and physical characteristics is scarce. Despite its frequently discussed importance in signaling, e.g., in obtaining localized non-homogeneous receptor compositions in the plasma membrane, the nanometer size as well as the dynamic and transient nature of domains impede their experimental characterization. In turn, atomistic molecular dynamics (MD) simulations combine both, high spatial and high temporal resolution. Here, using microsecond atomistic MD simulations, we characterize the spontaneous and unbiased formation of nano-domains in a plasma membrane model containing phosphatidylcholine (POPC), palmitoyl-sphingomyelin (PSM), and cholesterol (Chol) in the presence or absence of the neurotransmitter serotonin at different temperatures. In the ternary mixture, highly ordered and highly disordered domains of similar composition coexist at 303 K. The distinction of domains by lipid acyl chain order gets lost at lower temperatures of 298 and 294 K, suggesting a phase transition at ambient temperature. By comparison of domain ordering and composition, we demonstrate how the domain-specific binding of the neurotransmitter serotonin results in a modified domain lipid composition and a substantial downward shift of the phase transition temperature. Our simulations thus suggest a novel mode of action of neurotransmitters possibly of importance in neuronal signal transmission.

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In this work we present the coupling between Dry Martini, an efficient implicit solvent coarse-grained model for lipids, and the Lattice Boltzmann Molecular Dynamics (LBMD) simulation technique in order to include naturally hydrodynamic interactions in implicit solvent simulations of lipid systems. After validating the implementation of the model, we explored several systems where the action of a perturbing fluid plays an important role. Namely, we investigated the role of an external shear flow on the dynamics of a vesicle, the dynamics of substrate release under shear, and inquired the dynamics of proteins and substrates confined inside the core of a vesicle. Our methodology enables future exploration of a large variety of biological entities and processes involving lipid systems at the mesoscopic scale where hydrodynamics plays an essential role, e.g. by modulating the migration of proteins in the proximity of membranes, the dynamics of vesicle-based drug delivery systems, or, more generally, the behaviour of proteins in cellular compartments.

Tethering and homotypic fusion of mitochondrial outer membranes is mediated by large GTPases of the Dynamin-Related Proteins family called the mitofusins. The yeast mitofusin Fzo1 forms high molecular weight complexes and its assembly during membrane fusion likely involves the formation of high order complexes. Consistent with this possibility, mitofusins form oligomers in both cis (on the same lipid bilayer) and trans to mediate membrane attachment and fusion. Here, we rely on our recent Fzo1 model to investigate and discuss the formation of cis and trans mitofusin oligomers. We have built 3 cis-assembly Fzo1 models that gave rise to 3 distinct transoligomeric models of mitofusin constructs. Each model involves two main components of mitofusin oligomerization: the GTPase and the trunk domains. The oligomeric models proposed in this study were further assessed for stability and dynamics in a membrane environment using a coarse-grained molecular dynamics (MD) simulation approach. A narrow opening 'head-to-head' cisoligomerization (via the GTPase domain) followed by the antiparallel 'back-to-back' transassociations (via the trunk domain) appears to be in agreement with all the available experimental data. More broadly, this study opens new possibilities to start exploring cis and trans conformations for Fzo1 and mitofusins in general but also for other fusion-DRPs.

Mitochondria are dynamic organelles characterized by an ultrastructural organization which is essential in maintaining their quality control and ensure functional efficiency. The complex mitochondrial network is the result of the two ongoing forces of fusion and fission of inner and outer membranes. Understanding the functional details of mitochondrial dynamics is physiologically relevant as perturbations of this delicate equilibrium have critical consequences and involved in several neurological disorders. Molecular actors involved in this process are large GTPases from the dynamin-related protein family. They catalyze nucleotide-dependent membrane remodeling and are widely conserved from bacteria to higher eukaryotes. Although structural characterization of different family members has contributed to understand molecular mechanisms of mitochondrial dynamics in more detail, the complete structure of some members as well as the precise assembly of functional oligomers remain largely unknown. As increasing structural data becomes available, the domain modularity across the dynamin superfamily emerged as a foundation for transfer the knowledge towards less characterized members. In this review we will first provide an overview of the main actors involved in mitochondrial dynamics. We then discuss recent example of computational methodologies for the study of mitofusin oligomers, and present how the usage of integrative modeling in conjunction with biochemical data can be an asset in progress the still challenging field of membrane dynamics.