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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)
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)
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)
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)
Hairpins are a ubiquitous secondary structure motif in RNA molecules. Despite their simple structure, there is some debate over whether they fold in a two-state or multi-state manner. We have studied the folding of a small tetraloop hairpin using a serial version of replica exchange molecular dynamics on a distributed computing environment. On the basis of(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)
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)
Understanding molecular kinetics, and particularly protein folding, is a classic grand challenge in molecular biophysics. Network models, such as Markov state models (MSMs), are one potential solution to this problem. MSMs have recently yielded quantitative agreement with experimentally derived structures and folding rates for specific systems, leaving them(More)