Molecular Latent Space Simulators for Distributed and Multimolecular Trajectories.

All atom molecular dynamics (MD) simulations offer a powerful tool for molecular modeling, but the short time steps required for numerical stability of the integrator place many interesting molecular events out of reach of unbiased simulations. The popular and powerful Markov state modeling (MSM) approach can extend these time scales by stitching together multiple short discontinuous trajectories into a single long-time kinetic model but necessitates a configurational coarse-graining of the phase space that entails a loss of spatial and temporal resolution and an exponential increase in complexity for multimolecular systems. Latent space simulators (LSS) present an alternative formalism that employs a dynamical, as opposed to configurational, coarse graining comprising three back-to-back learning problems to (i) identify the molecular system's slowest dynamical processes, (ii) propagate the microscopic system dynamics within this slow subspace, and (iii) generatively reconstruct the trajectory of the system within the molecular phase space.

Predicting the structural basis of targeted protein degradation by integrating molecular dynamics simulations with structural mass spectrometry.

Targeted protein degradation (TPD) is a promising approach in drug discovery for degrading proteins implicated in diseases. A key step in this process is the formation of a ternary complex where a heterobifunctional molecule induces proximity of an E3 ligase to a protein of interest (POI), thus facilitating ubiquitin transfer to the POI. In this work, we characterize 3 steps in the TPD process.

Synaptotagmin rings as high-sensitivity regulators of synaptic vesicle docking and fusion.

Synchronous release at neuronal synapses is accomplished by a machinery that senses calcium influx and fuses the synaptic vesicle and plasma membranes to release neurotransmitters. Previous studies suggested the calcium sensor synaptotagmin (Syt) is a facilitator of vesicle docking and both a facilitator and inhibitor of fusion. On phospholipid monolayers, the Syt C2AB domain spontaneously oligomerized into rings that are disassembled by Ca, suggesting Syt rings may clamp fusion as membrane-separating "washers" until Ca-mediated disassembly triggers fusion and release [J.

The neuronal calcium sensor Synaptotagmin-1 and SNARE proteins cooperate to dilate fusion pores.

All membrane fusion reactions proceed through an initial fusion pore, including calcium-triggered release of neurotransmitters and hormones. Expansion of this small pore to release cargo is energetically costly and regulated by cells, but the mechanisms are poorly understood. Here, we show that the neuronal/exocytic calcium sensor Synaptotagmin-1 (Syt1) promotes expansion of fusion pores induced by SNARE proteins.

The role of scaffold reshaping and disassembly in dynamin driven membrane fission.

The large GTPase dynamin catalyzes membrane fission in eukaryotic cells, but despite three decades of experimental work, competing and partially conflicting models persist regarding some of its most basic actions. Here we investigate the mechanical and functional consequences of dynamin scaffold shape changes and disassembly with the help of a geometrically and elastically realistic simulation model of helical dynamin-membrane complexes. Beyond changes of radius and pitch, we emphasize the crucial role of a third functional motion: an effective rotation of the filament around its longitudinal axis, which reflects alternate tilting of dynamin's PH binding domains and creates a membrane torque.

SNARE-mediated membrane fusion is a two-stage process driven by entropic forces.

SNARE proteins constitute the core of the exocytotic membrane fusion machinery. Fusion occurs when vesicle-associated and target membrane-associated SNAREs zipper into trans-SNARE complexes ('SNAREpins'), but the number required is controversial and the mechanism of cooperative fusion is poorly understood. We developed a highly coarse-grained molecular dynamics simulation to access the long fusion timescales, which revealed a two-stage process.

Dynamin's helical geometry does not destabilize membranes during fission.

It is now widely accepted that dynamin-mediated fission is a fundamentally mechanical process: dynamin undergoes a GTP-dependent conformational change, constricting the neck between two compartments, somehow inducing their fission. However, the exact connection between dynamin's conformational change and the scission of the neck is still unclear. In this paper, we re-evaluate the suggestion that a change in the pitch or radius of dynamin's helical geometry drives the lipid bilayer through a mechanical instability, similar to a well-known phenomenon occurring in soap films.

Constriction by Dynamin: Elasticity versus Adhesion.

Any cellular fission process is completed when the neck connecting almost-separate membrane compartments is severed. This crucial step is somehow accomplished by proteins from the dynamin family, which polymerize into helical spirals around such necks. Much research has been devoted to elucidating the specifics of that somehow, but despite no shortage of ideas, the question is not settled.

Curvature Softening and Negative Compressibility of Gel-Phase Lipid Membranes.

We show that gel-phase lipid membranes soften upon bending, leading to curvature localization and a negative compressibility. Using simulations of two very different lipid models to quantify shape and stress-strain relation of buckled membranes, we demonstrate that gel phase bilayers do not behave like Euler elastica and hence are not well described by a quadratic Helfrich Hamiltonian, much unlike their fluid-phase counterparts. We propose a theoretical framework which accounts for the observed softening through an energy density that smoothly crosses over from a quadratic to a linear curvature dependence beyond a critical new scale [Formula: see text](-1).