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To date, the slowest-folding proteins folded ab initio by all-atom molecular dynamics simulations have had folding times in the range of nanoseconds to microseconds. We report simulations of several folding trajectories of NTL9(1-39), a protein which has a folding time of approximately 1.5 ms. Distributed molecular dynamics simulations in implicit solvent(More)
Biomolecular simulation is a core application on supercomputers, but it is exceptionally difficult to achieve the strong scaling necessary to reach biologically relevant timescales. Here, we present a new paradigm for parallel adaptive molecular dynamics and a publicly available implementation: Copernicus. This framework combines performance-leading(More)
Interleukin-15 (IL-15) and IL-2 possess distinct immunological functions despite both signaling through IL-2Rβ and the common cytokine receptor γ-chain, γ c , We find that in the IL-15— IL-15Rα—IL-2Rβ—γ c quaternary complex structure, IL-15 heterodimerizes IL-2Rβ and γ c identically to the IL-2—IL-2Rα—IL-2Rβ—γ c complex, despite differing receptor-binding(More)
Markov State Models provide a framework for understanding the fundamental states and rates in the conformational dynamics of biomolecules. We describe an improved protocol for constructing Markov State Models from molecular dynamics simulations. The new protocol includes advances in clustering, data preparation, and model estimation; these improvements lead(More)
Simulations can provide tremendous insight into the atomistic details of biological mechanisms, but micro- to millisecond timescales are historically only accessible on dedicated supercomputers. We demonstrate that cloud computing is a viable alternative that brings long-timescale processes within reach of a broader community. We used Google's Exacycle(More)
Characterization of transient intermediate or transition states is crucial for the description of biomolecular folding pathways, which is, however, difficult in both experiments and computer simulations. Such transient states are typically of low population in simulation samples. Even for simple systems such as RNA hairpins, recently there are mounting(More)
Molecular recognition is determined by the structure and dynamics of both a protein and its ligand, but it is difficult to directly assess the role of each of these players. In this study, we use Markov State Models (MSMs) built from atomistic simulations to elucidate the mechanism by which the Lysine-, Arginine-, Ornithine-binding (LAO) protein binds to(More)
We used custom-designed resequencing arrays to generate 3.1 Mb of genomic sequence from a panel of 56 Bacillus anthracis strains. Sequence quality was shown to be very high by replication (discrepancy rate of 7.4 x 10(-7)) and by comparison to independently generated shotgun sequence (discrepancy rate < 2.5 x 10(-6)). Population genomics studies of(More)
Protein folding is a classic grand challenge that is relevant to numerous human diseases, such as protein misfolding diseases like Alzheimer’s disease. Solving the folding problem will ultimately require a combination of theory, simulation, and experiment, with theory and simulation providing an atomically detailed picture of both the thermodynamics and(More)
Cryptic allosteric sites--transient pockets in a folded protein that are invisible to conventional experiments but can alter enzymatic activity via allosteric communication with the active site--are a promising opportunity for facilitating drug design by greatly expanding the repertoire of available drug targets. Unfortunately, identifying these sites is(More)