SPFP: Speed without compromise—A mixed precision model for GPU accelerated molecular dynamics simulations

Grand, Scott Le; Götz, Andreas W.; Walker, Ross C.

doi:10.1016/j.cpc.2012.09.022

Cited by 978 publications

(889 citation statements)

References 20 publications

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“…The program AMBER12 was used for the initial energyminimization, heating, and equilibration steps, using the pmemd.cuda module (88,89). Each system was energy-minimized, first with position restraints on the protein and ATP/Mg 2+ , and then without restraints.…”

Section: Methodsmentioning

confidence: 99%

Dynamic architecture of a protein kinase

McClendon

Kornev

Gilson

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

226

273

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To better understand the mechanism of long distance allosteric signaling inside the protein kinase core using protein kinase A (PKA) as a prototype, we obtained 5μs molecular dynamics trajectories in different liganded and conformational states using the Anton supercomputer, providing for the first time an opportunity to observe intermediate‐timescale conformational transitions in the study of the dynamics of this stable kinase. We used community analysis to identify structurally‐contiguous groups of residues exhibiting correlated motions in the kinase catalytic domain. This dynamic partitioning of the kinase into communities provides a framework for analyzing the local vs. long‐range effects of mutations, binding, phosphorylation, etc. We hypothesize that perturbations will be readily felt within these communities and then propagated possibly to a lesser extent to other elements through correlated motions. Moreover, using a wealth of published mutational data, we can annotate these communities with functions. Our functional annotation of kinase communities provides an extremely valuable framework for viewing a signaling enzyme in terms of functional substructures rather than isolated linear motifs such as secondary structure elements and short three or four residue motifs. Figure 1. Functional annotation of the kinase communitiy map. Each community is shown in red on the structure of PKA. Grant Funding Source: Supported by NIH F32 GM099197, R01 GM19301

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Section: Methodsmentioning

confidence: 99%

Dynamic architecture of a protein kinase

McClendon

Kornev

Gilson

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

226

273

View full text Add to dashboard Cite

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“…Simulations of other constructs were performed by modification of this starting system. Systems were equilibrated using standard equilibration protocols (41,81,82) in AMBER (83,84). Long timescale simulations were conducted on the Anton system with a 2-fs time step (85).…”

Section: Methodsmentioning

confidence: 99%

Slide-and-exchange mechanism for rapid and selective transport through the nuclear pore complex

Raveh

Karp

Sparks

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

131

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Nucleocytoplasmic transport is mediated by the interaction of transport factors (TFs) with disordered phenylalanine-glycine (FG) repeats that fill the central channel of the nuclear pore complex (NPC). However, the mechanism by which TFs rapidly diffuse through multiple FG repeats without compromising NPC selectivity is not yet fully understood. In this study, we build on our recent NMR investigations showing that FG repeats are highly dynamic, flexible, and rapidly exchanging among TF interaction sites. We use unbiased long timescale all-atom simulations on the Anton supercomputer, combined with extensive enhanced sampling simulations and NMR experiments, to characterize the thermodynamic and kinetic properties of FG repeats and their interaction with a model transport factor. Both the simulations and experimental data indicate that FG repeats are highly dynamic random coils, lack intrachain interactions, and exhibit significant entropically driven resistance to spatial confinement. We show that the FG motifs reversibly slide in and out of multiple TF interaction sites, transitioning rapidly between a strongly interacting state and a weakly interacting state, rather than undergoing a much slower transition between strongly interacting and completely noninteracting (unbound) states. In the weakly interacting state, FG motifs can be more easily displaced by other competing FG motifs, providing a simple mechanism for rapid exchange of TF/FG motif contacts during transport. This slide-and-exchange mechanism highlights the direct role of the disorder within FG repeats in nucleocytoplasmic transport, and resolves the apparent conflict between the selectivity and speed of transport.nuclear pore | molecular dynamics | nucleoporins | transport factors | NMR T he nuclear pore complex (NPC) regulates macromolecular transport between the nucleus and the cytoplasm in all eukaryotic cells (1, 2). The NPC allows for passive diffusion of small molecules including sugars, ions, and water, while simultaneously imposing size-dependent exclusion of macromolecules without nuclear transport factor (TF) binding sites, generating unique nuclear and cytoplasmic compartments (3, 4). Larger macromolecules can bypass the selectivity barrier of the NPC by interacting with TFs that shuttle cargo through the central channel of the pore. In pathological conditions, including many cancers and viral infections, the NPC is hijacked and used to transport undesired particles, or it is modified to attenuate the cellular responses to disease onset (5, 6).TFs traverse the NPC by selective and reversible association with disordered phenylalanine-glycine (FG) repeat domains of the FG nucleoporin proteins (FG Nups), which line the surface of the NPC (7-14). Each FG repeat domain consists of 5-50 FG repeats. In turn, each FG repeat consists of a single FG motif of various sequence flavors, such as the FSFG and GLFG motifs, and 10-30 spacer residues that separate consecutive FG motifs (15, 16). The spacer residues are strongly hydrophilic (17) and rich ...

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“…All simulations were performed using the GPU accelerated pmemd code (pmemd.cuda). [67][68][69] Only the last 20 ns (for proteins) or 80 ns (for DNA) of trajectories were kept and subjected to SAXS calculation.…”

Section: A MD Simulationsmentioning

confidence: 99%

Extracting water and ion distributions from solution x-ray scattering experiments

Nguyên

Pabit

Pollack

et al. 2016

The Journal of Chemical Physics

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Small-angle X-ray scattering measurements can provide valuable information about the solvent environment around biomolecules, but it can be difficult to extract solvent-specific information from observed intensity profiles. Intensities are proportional to the square of scattering amplitudes, which are complex quantities. Amplitudes in the forward direction are real, and the contribution from a solute of known structure (and from the waters it excludes) can be estimated from theory; hence, the amplitude arising from the solvent environment can be computed by difference. We have found that this "square root subtraction scheme" can be extended to non-zero q values, out to 0.1 Å −1 for the systems considered here, since the phases arising from the solute and from the water environment are nearly identical in this angle range. This allows us to extract aspects of the water and ion distributions (beyond their total numbers), by combining experimental data for the complete system with calculations for the solutes. We use this approach to test molecular dynamics and integral-equation (3D-RISM (three-dimensional reference interaction site model)) models for solvent structure around myoglobin, lysozyme, and a 25 base-pair duplex DNA. Comparisons can be made both in Fourier space and in terms of the distribution of interatomic distances in real space. Generally, computed solvent distributions arising from the MD simulations fit experimental data better than those from 3D-RISM, even though the total small-angle X-ray scattering patterns are very similar; this illustrates the potential power of this sort of analysis to guide the development of computational models. Published by AIP Publishing. [http://dx

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SPFP: Speed without compromise—A mixed precision model for GPU accelerated molecular dynamics simulations

Cited by 978 publications

References 20 publications

Dynamic architecture of a protein kinase

Dynamic architecture of a protein kinase

Slide-and-exchange mechanism for rapid and selective transport through the nuclear pore complex

Extracting water and ion distributions from solution x-ray scattering experiments

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