Dynamics of folded proteins

McCammon, J. Andrew; Gelin, Bruce R.; Karplus, Martin

doi:10.1038/267585a0

Cited by 1,792 publications

(1,171 citation statements)

References 37 publications

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“…In a paper in Nature, a team led by Martin Karplus published its 458-atom simulation of a tiny protein on an IBM 370, a top-of-the-line supercomputer 3 . Today, development teams around the world continue to work on CHARMM, or Chemistry at Harvard Molecular Mechanics, even as other algorithms such as NAMD have risen to compete with it.…”

Section: Pushing the Envelopementioning

confidence: 99%

Chemistry: Power play

Borrell¹

2008

Nature

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on computers running hundreds of parallel microprocessors to simulate how individual atoms behave in proteins and other large molecules. Schulten's group itself was working on a million-atom model of the satellite tobacco mosaic virus, which the researchers called "the first all-atom simulation of an entire life form" 1 .But the German-born physicist got his wakeup call in 2006, when he saw a table of computing benchmarks in a report from that year's supercomputing conference in Tampa, Florida. A new program called Desmond, he saw, could calculate each step of a standard moleculardynamics simulation -the 23,558 atoms in a system involving the protein dihydrofolate reductase -in a little over a thousandth of a second. NAMD was ten times slower. "Suddenly, "Schulten says, "we were not the best anymore. "The title had passed to the sender of the chocolates -David Shaw, a hedge-fund magnate and computer expert who taught himself physical chemistry. Over the previous few years, he had recruited more than 50 scientists and engineers, including three former students from Schulten's group, and put them to work in his midtown Manhattan high-rise.In the paper from the supercomputing conference, Shaw's team wrote that Desmond "is faster than NAMD at all levels of parallelism examined" 2 . And the group noted that on one simulation Desmond ran faster on 1,024 processors than NAMD ran on the 16,384 processors of IBM's Blue Gene/L -the world's fastest supercomputer.A German physicist and a hedge-fund magnate are competing to push protein simulations into the realm of the millisecond. Brendan Borrell finds out what is at stake.

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Section: Pushing the Envelopementioning

confidence: 99%

Chemistry: Power play

Borrell¹

2008

Nature

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“…For the case of pair computation (n = 2), in particular, shell-based methods-such as full-shell (FS), half-shell (HS), and eighth-shell (ES)-are used extensively for efficient search of pairs in Γ * (2) . These methods can be described systematically in terms of UCP.…”

Section: Relation To Previous Workmentioning

confidence: 99%

“…In one type of n-tuple computation (i.e. static n-tuple computation) used typically in biomolecular simulations [2], the list of atomic ntuples is fixed throughout the simulation. In another (i.e.…”

Section: Introductionmentioning

confidence: 99%

A scalable parallel algorithm for dynamic range-limited n -tuple computation in many-body molecular dynamics simulation

Kunaseth

Kalia

Nakano

et al. 2013

Proceedings of the International Conference on High Performance Computing, Networking, Storage and Analysis

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Recent advancements in reactive molecular dynamics (MD) simulations based on many-body interatomic potentials necessitate efficient dynamic n-tuple computation, where a set of atomic n-tuples within a given spatial range is constructed at every time step. Here, we develop a computation-pattern algebraic framework to mathematically formulate general n-tuple computation. Based on translation/reflection-invariant properties of computation patterns within this framework, we design a shiftcollapse (SC) algorithm for cell-based parallel MD. Theoretical analysis quantifies the compact n-tuple search space and small communication cost of SC-MD for arbitrary n, which are reduced to those in best pair-computation approaches (e.g. eighth-shell method) for n = 2. Benchmark tests show that SC-MD outperforms our production MD code at the finest grain, with 9.7-and 5.1-fold speedups on Intel-Xeon and BlueGene/Q clusters. SC-MD also exhibits excellent strong scalability.

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“…Following the first MD simulation of a protein 29 years ago (15) there were many successful applications in the study of structure and function of biological macromolecules (16,17). However, the standard MD technique faces a major limitation because of the so-called sampling problem (18).…”

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confidence: 99%

Entropic Folding Pathway of Human Epidermal Growth Factor Explored by Disulfide Scrambling and Amplified Collective Motion Simulations^,

Zhang

Boyle

et al. 2006

Biochemistry

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Epidermal growth factor (EGF) regulates cell proliferation and differentiation by binding to the EGF receptor (EGFR) extra-cellular domains. Human EGF is a small, single-chain protein comprising three distinct loops (A, B, and C), which are connected by three disulfide bridges (Cys6-Cys20, Cys14-Cys31, and Cys33-Cys42). These disulfide bridges are essential for structural stability and biological activity. EGF was extensively studied by disulfide scrambling, an experimental technique for the conformational entrapment of intermediate states, which allows us to study the folding pathway of proteins containing disulfide bonds. The experimental results showed that there is a major 2-disulfide intermediate (denoted EGF-II) and that the native disulfide bonding pattern is less prevalent in one of the mutants. In this article, we investigated for the first time the solution conformations of wild-type EGF, EGF-II, and the mutant S9C through extensive molecular dynamics (MD) simulations in water using both the standard MD technique and a recently developed amplified-collective-motion (ACM) sampling method. Compared to standard MD simulations, we achieved a much more enhanced sampling by the ACM simulations, and the structures were sufficiently relaxed to estimate configurational entropies. The simulation results suggest a predominantly entropic folding pathway governed by the disorder of three functional loop regions. Although EGF-II exhibits two native disulfide bonds (Cys14-Cys31 and Cys33-Cys42), its large configurational entropy inhibits a direct transition to the native structure in the folding process. When Ser9 is mutated into Cys, a non-native disulfide bridge Cys9-Cys20 is slightly more favorable than the native Cys6-Cys20 because a less constrained N-terminus affords larger entropy. Isomers that are functionally less active also exhibit a more localized dynamics of the functional loop regions, which may suggest a possible mechanism for the modulation of EGF activity.

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Dynamics of folded proteins

Cited by 1,792 publications

References 37 publications

Chemistry: Power play

Chemistry: Power play

A scalable parallel algorithm for dynamic range-limited n -tuple computation in many-body molecular dynamics simulation

Entropic Folding Pathway of Human Epidermal Growth Factor Explored by Disulfide Scrambling and Amplified Collective Motion Simulations^,

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Dynamics of folded proteins

Cited by 1,792 publications

References 37 publications

Chemistry: Power play

Chemistry: Power play

A scalable parallel algorithm for dynamic range-limited n -tuple computation in many-body molecular dynamics simulation

Entropic Folding Pathway of Human Epidermal Growth Factor Explored by Disulfide Scrambling and Amplified Collective Motion Simulations,

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Entropic Folding Pathway of Human Epidermal Growth Factor Explored by Disulfide Scrambling and Amplified Collective Motion Simulations^,