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RAS is a signaling protein associated with the cell membrane that is mutated in up to 30% of human cancers. RAS signaling has been proposed to be regulated by dynamic heterogeneity of the cell membrane. Investigating such a mechanism requires near-atomistic detail at macroscopic temporal and spatial scales, which is not possible with conventional computational or experimental techniques. We demonstrate here a multiscale simulation infrastructure that uses machine learning to create a scale-bridging ensemble of over 100,000 simulations of active wild-type KRAS on a complex, asymmetric membrane. Initialized and validated with experimental data (including a new structure of active wild-type KRAS), these simulations represent a substantial advance in the ability to characterize RAS-membrane biology. We report distinctive patterns of local lipid composition that correlate with interfacially promiscuous RAS multimerization. These lipid fingerprints are coupled to RAS dynamics, predicted to influence effector binding, and therefore may be a mechanism for regulating cell signaling cascades.

Patient-specific models of the ventricular myocardium, combined with the computational power to run rapid simulations, are approaching the level where they could be used for personalized cardiovascular medicine. A major remaining challenge is determining model parameters from available patient data, especially for models of the Purkinje-myocardial junctions (PMJs): the sites of initial ventricular electrical activation. There are no non-invasive methods for localizing PMJs in patients, and the relationship between the standard clinical ECG and PMJ model parameters is underexplored. Thus, this study aimed to determine the sensitivity of the QRS complex of the ECG to the anatomical location and regional number of PMJs. The QRS complex was simulated using an image-based human torso and biventricular model, and cardiac electrophysiology was simulated using Cardioid. The PMJs were modeled as discrete current injection stimuli, and the location and number of stimuli were varied within initial activation regions based on published experiments. Results indicate that the QRS complex features were most sensitive to the presence or absence of four "seed" stimuli, and adjusting locations of nearby "regional" stimuli provided finer tuning. Decreasing number of regional stimuli by an order of magnitude resulted in virtually no change in the QRS complex. Thus, a minimal 12-stimuli configuration was identified that resulted in physiological excitation, defined by QRS complex feature metrics and ventricular excitation pattern. Overall, the sensitivity results suggest that parameterizing PMJ location, rather than number, be given significantly higher priority in future studies creating personalized ventricular models from patient-derived ECGs.

We have implemented the Martini force field within Lawrence Livermore National Laboratory's molecular dynamics program, ddcMD. The program is extended to a heterogeneous programming model so that it can exploit graphics processing unit (GPU) accelerators. In addition to the Martini force field being ported to the GPU, the entire integration step, including thermostat, barostat, and constraint solver, is ported as well, which speeds up the simulations to 278-fold using one GPU vs one central processing unit (CPU) core. A benchmark study is performed with several test cases, comparing ddcMD and GROMACS Martini simulations. The average performance of ddcMD for a protein–lipid simulation system of 136k particles achieves 1.04 µs/day on one NVIDIA V100 GPU and aggregates 6.19 µs/day on one Summit node with six GPUs. The GPU implementation in ddcMD offloads all computations to the GPU and only requires one CPU core per simulation to manage the inputs and outputs, freeing up remaining CPU resources on the compute node for alternative tasks often required in complex simulation campaigns. The ddcMD code has been made open source and is available on GitHub at https://github.com/LLNL/ddcMD. [ABSTRACT FROM AUTHOR]

Keywords: massively parallel architectures; BlueGene/L; application scalability; performance study and optimization 33 Bluegene/l aPplications: Parallelism On a Massive Scale SAGE Publications, Inc.200810.1177/1094342007085025 Bronis R.de Supinski LAWRENCE LIVERMORE NATIONAL LABORATORY, LIVERMORE, […]

Medium-range interactions occur in a wide range of systems, including charged-particle systems with varying screening lengths. We generalize the Ewald method to charged systems described by interactions involving an arbitrary dielectric response function ∈(k). We provide an error estimate and optimize the generalization to find the break-even parameters that separate a neighbor list-only algorithm from the particle-particle particle-mesh algorithm.We examine the implications of different choices of the screening length for the computational cost of computing the dynamic structure factor. We then use our new method in molecular dynamics simulations to compute the dynamic structure factor for a model plasma system and examine thewave-dispersion properties of this system. [ABSTRACT FROM AUTHOR]

Reports that the diamond melting line was determined for a model system based on Brenner's bond order potential for hydrocarbon systems. Determination of the location of the first-order phase boundary by a free energy calculation of the diamond and liquid phases.

Constant temperature molecular dynamics has been used to simulate the adsorption of hydrated halide ions X-=F-, Cl-, Br- and I-, and lithium ion Li+ on flat uniformly charged surfaces. The simulations were done with either 214 water molecules and two ions (Li+ and X-) in a box 2.362 nm deep or with 430 water molecules and the two ions in a box 4.320 nm deep. The boxes were periodically replicated in the xy directions. The magnitude of the surface charge on the box ends was ±0.11 e/(nm)2, corresponding to an electric field of 2×107 V/cm. The lateral dimensions of the simulation cell were 1.862 nm×1.862 nm (x×y) in each case. All of the water molecules and ions interacted with the end walls via a weak 9-3 potential. The Stillinger ST2 water model and parameters optimized for alkali halides interacting with the model ST2 water molecule were used in the calculations. Common particles of truncating the interactions at a finite distance (0.82 nm) and switching off Coulomb interactions at small distances were followed. The temperature was set at T=2.411 kJ/mol (290 K). Some of the properties calculated were distribution density profiles for ions and water across the gap important for comparisons with Gouy–Chapman theory, adsorbed ion–water pair correlation functions, and the number of water molecules in the first and second hydration shells of the ions as a function of time. The time spent by a water molecule in the hydration shell was calculated to be approximately ten times longer for lithium than any other ion.The correlation between distance from the electrode and hydration number was studied and generally found to be pronounced for the larger anions. Comparison of the dynamics of the common ion Li+ for different anions revealed the subtle influence of a transcell interaction in the 2.362 nm thick film. In the given field, the smallest ions Li+ and F- remained fully solvated at all times. Chloride behaved quite differently. Part... [ABSTRACT FROM AUTHOR]

Molecular dynamics simulation of 216 water molecules (ST2 model) between charged flat electrodes 2.362 nm apart showed layering with a few molecules at each surface that broke H bonds with the bulk and oriented their charges towards the electrode. Compared to uncharged electrodes, the atomic and molecular distributions were unsymmetric. When a lithium and an iodide ion were substituted at random for two water molecules, the iodide ion contact adsorbed on the anode with no water molecules between it and the electrode. The iodide ion appeared weakly solvated on the solution side to water molecules that preferred to engage in hydrogen bonding with the network of the bulk solvent. In contrast, the lithium ion adsorbed without losing its primary solvation shell of six water molecules and was never observed further than two water molecules removed from the electrode. Its average position corresponded to an ion supported on a tripod of three waters. The average solvation number was not changed upon adsorption in this configuration. These qualitative observations and some quantitative results afford striking confirmation on the one hand and new insight on the other of some aspects of the standard model of the adsorption of ions on electrode surfaces. Time durations for simulations were generally between 200 and 800 ps with a basic integration time step of 2 fs. [ABSTRACT FROM AUTHOR]