Long-wavelength thermal fluctuations of lipid membranes are adequately described by the Helfrich elastic model. On the other hand, fluctuations of wavelengths comparable with bilayer thickness exhibit significant deviations from the prediction of the elastic model and are typically assumed to be dominated by microscopic surface tension due to protrusion of lipid molecules into the solvent. We present evidence that the short-wavelength modes of a lipid membrane are dominated by fluctuations of the tilt of lipid molecules with respect to the membrane normal rather than the microscopic surface tension. We obtain an expression for the spectral intensity of the thermal membrane fluctuations by appealing to the Hamm-Kozlov model, which accounts for both membrane bending and lipid tilt contributions to the total membrane energy but neglects the contributions of the microscopic surface tension. The tilt and the bending fluctuations obtained from our coarse-grained molecular dynamics simulations of a dipalmitoylphosphatidylcholine lipid bilayer show good agreement with the theory. Furthermore, the obtained tilt and bending moduli are in close agreement with experimentally determined values. The magnitude of the microscopic protrusion tension estimated from our simulations is significantly smaller than that of the tilt modulus. These results indicate that the membrane fluctuations can be adequately described by a macroscopic elastic model down to scales of interlipid distance provided one accounts for the tilt fluctuations.
Mitochondrial metabolic function is affected by the morphology and protein organization of the mitochondrial inner membrane. Cardiolipin (CL) is a unique tetra-acyl lipid that is involved in the maintenance of the highly curved shape of the mitochondrial inner membrane as well as spatial organization of the proteins necessary for respiration and oxidative phosphorylation. Cardiolipin has been suggested to self-organize into lipid domains due to its inverted conical molecular geometry, though the driving forces for this organization are not fully understood. In this work, we use coarse-grained molecular dynamics simulations to study the mechanical properties and lipid dynamics in heterogeneous bilayers both with and without CL, as a function of membrane curvature. We find that incorporation of CL increases bilayer deformability and that CL becomes highly enriched in regions of high negative curvature. We further show that another mitochondrial inverted conical lipid, phosphatidylethanolamine (PE), does not partition or increase the deformability of the membrane in a significant manner. Therefore, CL appears to possess some unique characteristics that cannot be inferred simply from molecular geometry considerations.
Mitochondrial dysfunction underlies many heritable diseases, acquired pathologies, and aging-related declines in health. Szeto–Schiller (SS) peptides comprise a class of amphipathic tetrapeptides that are efficacious toward a wide array of mitochondrial disorders and are believed to target mitochondrial membranes because they are enriched in the anionic phospholipid cardiolipin (CL). However, little is known regarding how SS peptides interact with or alter the physical properties of lipid bilayers. In this study, using biophysical and computational approaches, we have analyzed the interactions of the lead compound SS-31 (elamipretide) with model and mitochondrial membranes. Our results show that this polybasic peptide partitions into the membrane interfacial region with an affinity and a lipid binding density that are directly related to surface charge. We found that SS-31 binding does not destabilize lamellar bilayers even at the highest binding concentrations; however, it did cause saturable alterations in lipid packing. Most notably, SS-31 modulated the surface electrostatics of both model and mitochondrial membranes. We propose nonexclusive mechanisms by which the tuning of surface charge could underpin the mitoprotective properties of SS-31, including alteration of the distribution of ions and basic proteins at the interface, and/or modulation of bilayer physical properties. As a proof of concept, we show that SS-31 alters divalent cation (calcium) distribution within the interfacial region and reduces the energetic burden of calcium stress in mitochondria. The mechanistic details of SS-31 revealed in this study will help inform the development of future compound variants with enhanced efficacy and bioavailability.
Capsid maturation with large-scale subunit reorganization occurs in virtually all viruses that use a motor to package nucleic acid into preformed particles. A variety of ensemble studies indicate that the particles gain greater stability during this process, however, it is unknown which material properties of the fragile procapsids change. Using Atomic Force Microscopy-based nano-indentation, we study the development of the mechanical properties during maturation of bacteriophage HK97, a λ-like phage of which the maturationinduced morphological changes are well described. We show that mechanical stabilization and strengthening occurs in three independent ways: (i) an increase of the Young's modulus, (ii) a strong rise of the capsid's ultimate strength, and (iii) a growth of the resistance against material fatigue. The Young's modulus of immature and mature capsids, as determined from thin shell theory, fit with the values calculated using a new multiscale simulation approach. This multiscale calculation shows that the increase in Young's modulus isn't dependent on the crosslinking between capsomers. In contrast, the ultimate strength of the capsids does increase even when a limited number of cross-links are formed while full crosslinking appears to protect the shell against material fatigue. Compared to phage λ, the covalent crosslinking at the icosahedral and quasi threefold axes of HK97 yields a mechanically more robust particle than the addition of the gpD protein during maturation of phage λ. These results corroborate the expected increase in capsid stability and strength during maturation, however in an unexpected intricate way, underlining the complex structure of these self-assembling nanocontainers.AFM | elastic network model | nanoindentation | normal mode analysis | virus structural mechanics H K97 is a double stranded DNA bacteriophage infecting Escherichia coli. The capsid protein of HK97 has a subunit fold that is shared by phages λ, P22, T4, and phi29, among others, as well as the eukaryotic virus, Herpes (1). In addition, the maturation pathways of these viruses show similar morphological changes (2). HK97 provides a unique model system to study capsid maturation, as large quantities of isometric particles can be produced in an E. coli expression system. These particles are expressed without the portal and terminase proteins used for genome packaging, but can be isolated as procapsids and matured in vitro using chemical agents instead of DNA, and maturation can be trapped in various expansion states (3, 4). In vitro expansion can be effectively induced with a variety of chemical agents, including lowering the pH below 4. The particles expand from the Prohead II (P-II) form, which differs from Prohead I (P-I) by the absence of the 104AA N-terminal polypeptide (termed the Δ-domain) from each subunit (gp5). The Δ-domain is presumed to function in scaffolding capsid assembly (5, 6). The Δ-domain is cleaved by an internally packaged protease (gp4) upon assembly, allowing the particle transition to the ...
The propensity for capsid disassembly and uncoating of human adenovirus is modulated by interactions with host cell molecules like integrins and alpha defensins. Here, we use atomic force microscopy (AFM) nanoindentation to elucidate, at the single-particle level, the mechanism by which binding of these host molecules affects virus particle elasticity. Our results demonstrate the direct link between integrin or defensin binding and the mechanical properties of the virus. We show that the structure and geometry of adenovirus result in an anisotropic elastic response that relates to icosahedral symmetry. This elastic response changes upon binding host molecules. Whereas integrin binding softens the vertex regions, binding of a human alpha defensin has exactly the opposite effect. Our results reveal that the ability of these host molecules to influence adenovirus disassembly correlates with a direct effect on the elastic strength of the penton region. Host factors that influence adenovirus infectivity thus modulate the elastic properties of the capsid. Our findings reveal a direct link between virus-host interactions and capsid mechanics. Human adenovirus (HAdV) is one of the largest known nonenveloped double-stranded DNA (dsDNA) viruses. The ϳ36-kb viral genome is encapsidated by a pseudo-Tϭ25 icosahedral capsid that is over 90 nm in diameter with a corresponding mass of ϳ150 MDa (1-3). The main capsid proteins form a closed icosahedral shell that is composed of 240 trimeric hexons, 12 pentamers of the penton base, and 12 fiber trimers. In addition, there are four cement capsid proteins (IIIa, VI, VIII, and IX) and five proteins associated with the genomic core of the virion (V, VII, , IVa2, and terminal protein). During the final step of particle maturation, multiple capsid proteins are posttranslationally processed by a viral protease. Approximately one-third of the more than 50 adenovirus types cause acute infections in humans that are generally self-limiting except in immunocompromised patients. Replication-defective adenoviruses are also used in a significant number of gene therapy and vaccine applications (4).Integrin ␣v5 is one of several cell surface receptors for adenovirus that mediates internalization of the virus rather than attachment (5-7). Adenovirus binding to integrin ␣v5 promotes clustering of the receptors and activates downstream signaling pathways that facilitate virus endocytosis. Integrin binds to exposed RGD motifs on the virus penton base in a maximum stoichiometry of 4:5 (8, 9). This stoichiometric mismatch between integrin ␣v5 and the penton base is the result of a steric hindrance. It is also believed that integrin binding causes a conformation change in the penton base. The spiral untwisting of the penton base protein due to integrin binding could relax the interactions of the individual penton base subunits with the neighboring peripentonal hexons as well as cause the release of the fiber protein at the cell surface, thereby facilitating capsid disassembly at a later stage of cell ...
We apply two-dimensional elasticity theory to viral capsids to develop a framework for calculating elastic properties of viruses from equilibrium thermal fluctuations of the capsid surface in molecular dynamics and elastic network model trajectories. We show that the magnitudes of the long wavelength modes of motion available in a simulation with all atomic degrees of freedom are recapitulated by an elastic network model. For the mode spectra to match, the elastic network model must be scaled appropriately by a factor which can be determined from an icosahedrally constrained all-atom simulation. With this method we calculate the two-dimensional Young’s modulus Y, bending modulus κ, and Föppl–von Kármán number γ, for the T = 1 mutant of the Sesbania mosaic virus. The values determined are in the range of previous theoretical estimates.
The mitochondrial lipid cardiolipin (CL) contributes to the spatial protein organization and morphological character of the inner mitochondrial membrane. Monolysocardiolipin (MLCL), an intermediate species in the CL remodeling pathway, is enriched in the multisystem disease Barth syndrome. Despite the medical relevance of MLCL, a detailed molecular description that elucidates the structural and dynamic differences between CL and MLCL has not been conducted. To this end, we performed comparative atomistic molecular dynamics studies on bilayers consisting of pure CL or MLCL to elucidate similarities and differences in their molecular and bulk bilayer properties. We describe differential headgroup dynamics and hydrogen bonding patterns between the CL variants and show an increased cohesiveness of MLCL's solvent interfacial region, which may have implications for protein interactions. Finally, using the coarse-grained Martini model, we show that substitution of MLCL for CL in bilayers mimicking mitochondrial composition induces drastic differences in bilayer mechanical properties and curvature-dependent partitioning behavior. Together, the results of this work reveal differences between CL and MLCL at the molecular and mesoscopic levels that may underpin the pathomechanisms of defects in cardiolipin remodeling.
Cardiolipin mediates dynamic receptor-channel interactions within the mitochondrial TIM23 protein import complex.
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