Three parallel algorithms for classical molecular dynamics are presented. The first assigns each processor a fixed subset of atoms; the second assigns each a fixed subset of inter-atomic forces to compute; the third assigns each a fixed spatial region. The algorithms are suitable for molecular dynamics models which can be difficult to parallelize efficiently—those with short-range forces where the neighbors of each atom change rapidly. They can be implemented on any distributed-memory parallel machine which allows for message-passing of data between independently executing processors. The algorithms are tested on a standard Lennard-Jones benchmark problem for system sizes ranging from 500 to 100,000,000 atoms on several parallel supercomputers--the nCUBE 2, Intel iPSC/860 and Paragon, and Cray T3D. Comparing the results to the fastest reported vectorized Cray Y-MP and C90 algorithm shows that the current generation of parallel machines is competitive with conventional vector supercomputers even for small problems. For large problems, the spatial algorithm achieves parallel efficiencies of 90% and a 1840-node Intel Paragon performs up to 165 faster than a single Cray C9O processor. Trade-offs between the three algorithms and guidelines for adapting them to more complex molecular dynamics simulations are also discussed.

Fast parallel algorithms for short-range molecular dynamics

다중혈관 관상동맥 환자에서 y-문합을 이용하여 양쪽 내흉동맥만을 사용한 우회술의 조기 성적

抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Molecular simulation is an extremely useful, but computationally very expensive tool for studies of chemical and biomolecular systems Here, we present a new implementation of our molecular simulation toolkit GROMACS which now both achieves extremely high performance on single processors from algorithmic optimizations and hand-coded routines and simultaneously scales very well on parallel machines The code encompasses a minimal-communication domain decomposition algorithm, full dynamic load balancing, a state-of-the-art parallel constraint solver, and efficient virtual site algorithms that allow removal of hydrogen atom degrees of freedom to enable integration time steps up to 5 fs for atomistic simulations also in parallel To improve the scaling properties of the common particle mesh Ewald electrostatics algorithms, we have in addition used a Multiple-Program, Multiple-Data approach, with separate node domains responsible for direct and reciprocal space interactions Not only does this combination of a

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GROMACS 4: Algorithms for highly efficient, load-balanced, and scalable molecular simulation

New developments in the science of learning science of learning overview mind and brain how experts differ from novices how children learn learning and transfer the learning environment curriculum, instruction and commnity effective teaching - examples in history, mathematics and science teacher learning technology to support learning conclusions from new developments in the science of learning.

How people learn: Brain, mind, experience, and school.

Drug-resistant variants of thymidylate synthase (TS) can potentially be used in gene therapy applications to decrease the myelosuppressive side effects of TS-directed anticancer agents or to select genetically modified cells in vivo. Mutations of proline 303 of human TS confer resistance to TS-directed fluoropyrimidines and antifolates (Kitchens et al., 1999). We generated the corresponding variants in Escherichia coli TS (ecTS), position 254, to better understand the mechanism by which mutations at this residue confer resistance. In addition, because ecTS is intrinsically resistant to several antifolates when compared with human TS, we suspected that greater resistance could be achieved with the bacterial enzyme. The P254L enzyme conferred >100-fold resistance to both raltitrexed and 5-fluoro-2′-deoxyuridine (FdUrd) compared with wild-type ecTS. Four additional mutants (P254F, P254S, P254G, and P254D), each of which complemented growth of a TS-deficient cell line, were generated, isolated, and characterized. Steady-state values of K m for dUMP and k cat were not substantially different among the variants and were comparable with the wild-type values, but K m for methylenetetrahydrofolate (CH 2 H 4 PteGlu) was >10-fold higher for P254D. Values of k on and k off for nucleotide binding, which were obtained by stopped-flow spectroscopy, were virtually unchanged among the mutants. Drastic differences were observed for CH 2 H 4 PteGlu binding, with K d values >15-fold higher than observed with the wild-type enzyme; surprisingly, the proposed isomerization reaction that is very evident for the wild-type enzyme is not observed with P254S. The decrease in affinity for CH 2 H 4 PteGlu correlates well with K i values obtained for three TS-directed inhibitors. These results show that mutations at Pro-254 specifically affect the initial binding interactions between enzyme and cofactor and also alter the ability of the mutant enzymes to undergo conformational changes that occur on ternary complex formation. The crystal structure of P254S was determined at 1.5 A resolution and is the most precise structure of TS available. When compared with wild-type TS, the structure shows local conformational changes affecting mostly Asp-253; its carbonyl is rotated approximately 40°, and the side chain forms an ion pair with Arg-225.

Drug-resistant variants of Escherichia coli thymidylate synthase: effects of substitutions at Pro-254.

NON-VON is a highly parallel machine designed to support the efficient implementation of very large scale knowledge-based systems. The utility of such a machine has been demonstrated analytically [1, 2] and through implementation of a working knowledge-based information retrieval system in which the NON-VON machine instructions were emulated in software [3]. In cooperation with the Stanford Computer Science Department, we have recently begun to implement the most important components of the machine as custom VLSI circuits.

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NON-VON: a parallel machine architecture for knowledge-based information processing

The present invention provides for an assay that identifies kinase inhibitors by employing fluorescence resonance energy transfer in a competition binding approach.

Fret-based binding assay

Molecular simulations aim to sample all of the thermodynamically important states; when the sampling is inadequate, inaccuracy follows. A widely used technique to enhance sampling in simulations is Hamiltonian exchange. This technique introduces auxiliary Hamiltonians under which sampling is computationally efficient and attempts to exchange the molecular states among the auxiliary and the original Hamiltonians. The effectiveness of Hamiltonian exchange depends in part on the probability that the trial exchanges can be accepted, which involves good choices of auxiliary Hamiltonians and a good method of generating the trial exchanges. In this paper, we investigate nonequilibrium simulations as trial exchange generators and develop a theoretical model for the efficiency of Hamiltonian exchange and an algorithm to better configure such simulations. We show that properly configured nonequilibrium simulations can modestly increase the overall efficiency of Hamiltonian exchange.

Improving Sampling by Exchanging Hamiltonians with Efficiently Configured Nonequilibrium Simulations

Drug resistance gene therapy has the potential to protect against the myelosuppressive side effects of chemotherapy or to be used as a dominant in vivo selectable marker of genetically modified cells. Steady state kinetic studies have indicated the Escherichia coli thymidylate synthase (ecTS) is intrinsically more resistant to several TS-directed inhibitors as compared with the human enzyme, suggesting that ecTS is suitable for use as a drug-resistant marker. However, we found a disparity between the kinetic properties of ecTS and the degree of resistance conferred to cells transfected with the cDNA encoding this enzyme. It was determined that although ecTS is as stable as human TS (hTS) in transfected mammalian cells, ecTS is produced at only 40% the level of hTS, indicating poor translation of ecTS in eukaryotic cells. To circumvent this problem, the entire cDNA sequence of ecTS was synthesized by using codons optimized for expression in mammalian cells. In transfected Chinese hamster lung cells, expression of ecTS from the optimized construct, termed OPTecTS, is as efficient as hTS. Furthermore, cells transfected with the OPTecTS cDNA are significantly more resistant to the TS inhibitor raltitrexed as compared with transfected cells expressing similar levels of hTS. High-titer retroviral packaging cells were generated with OPTecTS and >80% of transduced mouse hematopoietic progenitor cells are resistant to raltitrexed, Thymitaq, and U89 at concentrations that eliminated colony growth of mock-transduced cells. The transgene was detectable by PCR in transduced bone marrow selected in U89 or raltitrexed, and expression of ecTS from the OPTecTS cDNA in bone marrow exhibited a catalytic rate constant comparable to that of purified recombinant ecTS. These data indicate that OPTecTS is a viable dominant selectable marker that can confer resistance to antifolates when introduced into cells.

David E. Shaw

Papers

Drug-resistant variants of Escherichia coli thymidylate synthase: effects of substitutions at Pro-254.

NON-VON: a parallel machine architecture for knowledge-based information processing

Fret-based binding assay

Improving Sampling by Exchanging Hamiltonians with Efficiently Configured Nonequilibrium Simulations

Retroviral expression of Escherichia coli thymidylate synthase cDNA confers high-level antifolate resistance to hematopoietic cells.