Membrane-Protein Interactions in a Generic Coarse-Grained Model for Lipid Bilayers

We study membrane-protein interactions and membrane-mediated protein-protein interactions by Monte Carlo simulations of a generic coarse-grained model for lipid bilayers with cylindrical hydrophobic inclusions. The strength of the hydrophobic force and the hydrophobic thickness of the proteins are systematically varied. The results are compared with analytical predictions of two popular analytical theories: The Landau-de Gennes theory and the elastic theory. The elastic theory provides an excellent description of the fluctuation spectra of pure membranes and successfully reproduces the deformation profiles of membranes around single proteins. However, its prediction for the potential of mean force between proteins is not compatible with the simulation data for large distances. The simulations show that the lipid-mediated interactions are governed by five competing factors: Direct interactions, lipid-induced depletion interactions, lipid bridging, lipid packing, and a smooth long-range contribution. The mechanisms leading to "hydrophobic mismatch" interactions are critically analyzed.Comment: 16 pages, 8 figures, accepted for publication in Biophysical Journa

TREBUCHET: Fully Homomorphic Encryption Accelerator for Deep Computation

Secure computation is of critical importance to not only the DoD, but across financial institutions, healthcare, and anywhere personally identifiable information (PII) is accessed. Traditional security techniques require data to be decrypted before performing any computation. When processed on untrusted systems the decrypted data is vulnerable to attacks to extract the sensitive information. To address these vulnerabilities Fully Homomorphic Encryption (FHE) keeps the data encrypted during computation and secures the results, even in these untrusted environments. However, FHE requires a significant amount of computation to perform equivalent unencrypted operations. To be useful, FHE must significantly close the computation gap (within 10x) to make encrypted processing practical. To accomplish this ambitious goal the TREBUCHET project is leading research and development in FHE processing hardware to accelerate deep computations on encrypted data, as part of the DARPA MTO Data Privacy for Virtual Environments (DPRIVE) program. We accelerate the major secure standardized FHE schemes (BGV, BFV, CKKS, FHEW, etc.) at >=128-bit security while integrating with the open-source PALISADE and OpenFHE libraries currently used in the DoD and in industry. We utilize a novel tile-based chip design with highly parallel ALUs optimized for vectorized 128b modulo arithmetic. The TREBUCHET coprocessor design provides a highly modular, flexible, and extensible FHE accelerator for easy reconfiguration, deployment, integration and application on other hardware form factors, such as System-on-Chip or alternate chip areas.Comment: 6 pages, 5figures, 2 table

Curvature-coupling dependence of membrane protein diffusion coefficients

We consider the lateral diffusion of a protein interacting with the curvature of the membrane. The interaction energy is minimized if the particle is at a membrane position with a certain curvature that agrees with the spontaneous curvature of the particle. We employ stochastic simulations that take into account both the thermal fluctuations of the membrane and the diffusive behavior of the particle. In this study we neglect the influence of the particle on the membrane dynamics, thus the membrane dynamics agrees with that of a freely fluctuating membrane. Overall, we find that this curvature-coupling substantially enhances the diffusion coefficient. We compare the ratio of the projected or measured diffusion coefficient and the free intramembrane diffusion coefficient, which is a parameter of the simulations, with analytical results that rely on several approximations. We find that the simulations always lead to a somewhat smaller diffusion coefficient than our analytical approach. A detailed study of the correlations of the forces acting on the particle indicates that the diffusing inclusion tries to follow favorable positions on the membrane, such that forces along the trajectory are on average smaller than they would be for random particle positions.Comment: 16 pages, 8 figure

Variational Methods for Biomolecular Modeling

Structure, function and dynamics of many biomolecular systems can be characterized by the energetic variational principle and the corresponding systems of partial differential equations (PDEs). This principle allows us to focus on the identification of essential energetic components, the optimal parametrization of energies, and the efficient computational implementation of energy variation or minimization. Given the fact that complex biomolecular systems are structurally non-uniform and their interactions occur through contact interfaces, their free energies are associated with various interfaces as well, such as solute-solvent interface, molecular binding interface, lipid domain interface, and membrane surfaces. This fact motivates the inclusion of interface geometry, particular its curvatures, to the parametrization of free energies. Applications of such interface geometry based energetic variational principles are illustrated through three concrete topics: the multiscale modeling of biomolecular electrostatics and solvation that includes the curvature energy of the molecular surface, the formation of microdomains on lipid membrane due to the geometric and molecular mechanics at the lipid interface, and the mean curvature driven protein localization on membrane surfaces. By further implicitly representing the interface using a phase field function over the entire domain, one can simulate the dynamics of the interface and the corresponding energy variation by evolving the phase field function, achieving significant reduction of the number of degrees of freedom and computational complexity. Strategies for improving the efficiency of computational implementations and for extending applications to coarse-graining or multiscale molecular simulations are outlined.Comment: 36 page

Interactions Between a Voltage Sensor and a Toxin via Multiscale Simulations

Gating-modifier toxins inhibit voltage-gated ion channels by binding the voltage sensors (VS) and altering the energetics of voltage-dependent gating. These toxins are thought to gain access to the VS via the membrane (i.e., by partitioning from water into the membrane before binding the VS). We used serial multiscale molecular-dynamics (MD) simulations, via a combination of coarse-grained (CG) and atomistic (AT) simulations, to study how the toxin VSTx1, which inhibits the archeabacterial voltage-gated potassium channel KvAP, interacts with an isolated membrane-embedded VS domain. In the CG simulations, VSTx1, which was initially located in water, partitioned into the headgroup/water interface of the lipid bilayer before binding the VS. The CG configurations were used to generate AT representations of the system, which were subjected to AT-MD to further evaluate the stability of the complex and refine the predicted VS/toxin interface. VSTx1 interacted with a binding site on the VS formed by the C-terminus of S1, the S1-S2 linker, and the N-terminus of S4. The predicted VS/toxin interactions are suggestive of toxin-mediated perturbations of the interaction between the VS and the pore domain of Kv channels, and of the membrane. Our simulations support a membrane-access mechanism of inhibition of Kv channels by VS toxins. Overall, the results show that serial multiscale MD simulations may be used to model a two-stage process of protein-bilayer and protein-protein interactions within a membrane

Membrane curvature during peroxisome fission requires Pex11

Pex11p is required for peroxisome proliferation. This study demonstrates that the N-terminus of Pex11p forms an amphipathic helix that generates membrane curvature required for peroxisome fission

Programmed Bending Reveals Dynamic Mechanochemical Coupling in Supported Lipid Bilayers

In living cells, mechanochemical coupling represents a dynamic means by which membrane components are spatially organized. An extra-ordinary example of such coupling involves curvature-dependent polar localization of chemically-distinct lipid domains at bacterial poles, which also undergo dramatic reequilibration upon subtle changes in their interfacial environment such as during sporulation. Here, we demonstrate that such interfacially-triggered mechanochemical coupling can be recapitulated in vitro by simultaneous, real-time introduction of mechanically-generated periodic curvatures and attendant strain-induced lateral forces in lipid bilayers supported on elastomeric substrates. In particular, we show that real-time wrinkling of the elastomeric substrate prompts a dynamic domain reorganization within the adhering bilayer, producing large, oriented liquid-ordered domains in regions of low curvature. Our results suggest a mechanism in which interfacial forces generated during surface wrinkling and the topographical deformation of the bilayer combine to facilitate dynamic reequilibration prompting the observed domain reorganization. We anticipate this curvature-generating model system will prove to be a simple and versatile tool for a broad range of studies of curvature-dependent dynamic reorganizations in membranes that are constrained by the interfacial elastic and dynamic frameworks such as the cell wall, glycocalyx, and cytoskeleton

Sar1 assembly regulates membrane constriction and ER export

While dynamin pinches vesicles from the plasma membrane, the Sar1 GTPase specializes in cinching ER membrane tubules

RPU: The Ring Processing Unit

Ring-Learning-with-Errors (RLWE) has emerged as the foundation of many important techniques for improving security and privacy, including homomorphic encryption and post-quantum cryptography. While promising, these techniques have received limited use due to their extreme overheads of running on general-purpose machines. In this paper, we present a novel vector Instruction Set Architecture (ISA) and microarchitecture for accelerating the ring-based computations of RLWE. The ISA, named B512, is developed to meet the needs of ring processing workloads while balancing high-performance and general-purpose programming support. Having an ISA rather than fixed hardware facilitates continued software improvement post-fabrication and the ability to support the evolving workloads. We then propose the ring processing unit (RPU), a high-performance, modular implementation of B512. The RPU has native large word modular arithmetic support, capabilities for very wide parallel processing, and a large capacity high-bandwidth scratchpad to meet the needs of ring processing. We address the challenges of programming the RPU using a newly developed SPIRAL backend. A configurable simulator is built to characterize design tradeoffs and quantify performance. The best performing design was implemented in RTL and used to validate simulator performance. In addition to our characterization, we show that a RPU using 20.5mm2 of GF 12nm can provide a speedup of 1485x over a CPU running a 64k, 128-bit NTT, a core RLWE workloa

Minimal Mesoscale Model for Protein-Mediated Vesiculation in Clathrin-Dependent Endocytosis

In eukaryotic cells, the internalization of extracellular cargo via the endocytic machinery is an important regulatory process required for many essential cellular functions. The role of cooperative protein-protein and protein-membrane interactions in the ubiquitous endocytic pathway in mammalian cells, namely the clathrin-dependent endocytosis, remains unresolved. We employ the Helfrich membrane Hamiltonian together with surface evolution methodology to address how the shapes and energetics of vesicular-bud formation in a planar membrane are stabilized by presence of the clathrin-coat assembly. Our results identify a unique dual role for the tubulating protein epsin: multiple epsins localized spatially and orientationally collectively play the role of a curvature inducing capsid; in addition, epsin serves the role of an adapter in binding the clathrin coat to the membrane. Our results also suggest an important role for the clathrin lattice, namely in the spatial- and orientational-templating of epsins. We suggest that there exists a critical size of the coat above which a vesicular bud with a constricted neck resembling a mature vesicle is stabilized. Based on the observed strong dependence of the vesicle diameter on the bending rigidity, we suggest that the variability in bending stiffness due to variations in membrane composition with cell type can explain the experimentally observed variability on the size of clathrin-coated vesicles, which typically range 50–100 nm. Our model also provides estimates for the number of epsins involved in stabilizing a coated vesicle, and without any direct fitting reproduces the experimentally observed shapes of vesicular intermediates as well as their probability distributions quantitatively, in wildtype as well as CLAP IgG injected neuronal cell experiments. We have presented a minimal mesoscale model which quantitatively explains several experimental observations on the process of vesicle nucleation induced by the clathrin-coated assembly prior to vesicle scission in clathrin dependent endocytosis