Showing papers by "D. E. Shaw Research published in 2006"

Scalable algorithms for molecular dynamics simulations on commodity clusters

Abstract: Although molecular dynamics (MD) simulations of biomolecular systems often run for days to months, many events of great scientific interest and pharmaceutical relevance occur on long time scales that remain beyond reach. We present several new algorithms and implementation techniques that significantly accelerate parallel MD simulations compared with current stateof- the-art codes. These include a novel parallel decomposition method and message-passing techniques that reduce communication requirements, as well as novel communication primitives that further reduce communication time. We have also developed numerical techniques that maintain high accuracy while using single precision computation in order to exploit processor-level vector instructions. These methods are embodied in a newly developed MD code called Desmond that achieves unprecedented simulation throughput and parallel scalability on commodity clusters. Our results suggest that Desmond?s parallel performance substantially surpasses that of any previously described code. For example, on a standard benchmark, Desmond?s performance on a conventional Opteron cluster with 2K processors slightly exceeded the reported performance of IBM?s Blue Gene/L machine with 32K processors running its Blue Matter MD code.

A non–RGD-based integrin binding peptide (ATN-161) blocks breast cancer growth and metastasis in vivo

Abstract: Purpose: Integrins are expressed by numerous tumor types including breast cancer, in which they play a crucial role in tumor growth and metastasis. In this study, we evaluated the ability of ATN-161 (Ac-PHSCN-NH2), a 5-mer capped peptide derived from the synergy region of fibronectin that binds to α5β1 and αvβ3 in vitro , to block breast cancer growth and metastasis. Experimental design: MDA-MB-231 human breast cancer cells were inoculated s.c. in the right flank, or cells transfected with green fluorescent protein (MDA-MB-231-GFP) were inoculated into the left ventricle of female BALB/c nu/nu mice, resulting in the development of skeletal metastasis. Animals were treated with vehicle alone or by i.v. infusion with ATN-161 (0.05–1 mg/kg thrice a week) for 10 weeks. Tumor volume was determined at weekly intervals and tumor metastasis was evaluated by X-ray, microcomputed tomography, and histology. Tumors were harvested for histologic evaluation. Result: Treatment with ATN-161 caused a significant dose-dependent decrease in tumor volume and either completely blocked or caused a marked decrease in the incidence and number of skeletal as well as soft tissue metastases. This was confirmed histologically as well as radiographically using X-ray and microcomputed tomography. Treatment with ATN-161 resulted in a significant decrease in the expression of phosphorylated mitogen-activated protein kinase, microvessel density, and cell proliferation in tumors grown in vivo. Conclusion: These studies show that ATN-161 can block breast cancer growth and metastasis, and provides a rationale for the clinical development of ATN-161 for the treatment of breast cancer. [Mol Cancer Ther 2006;5(9):2271–80]

Copper Binding by Tetrathiomolybdate Attenuates Angiogenesis and Tumor Cell Proliferation through the Inhibition of Superoxide Dismutase 1

Abstract: Purpose: A second-generation tetrathiomolybdate analogue (ATN-224; choline tetrathiomolybdate), which selectively binds copper with high affinity, is currently completing two phase I clinical trials in patients with advanced solid and advanced hematologic malignancies. However, there is very little information about the mechanism of action of ATN-224 at the molecular level. Experimental Design: The effects of ATN-224 on endothelial and tumor cell growth were evaluated in cell culture experiments in vitro . The antiangiogenic activity of ATN-224 was investigated using the Matrigel plug model of angiogenesis. Results: ATN-224 inhibits superoxide dismutase 1 (SOD1) in tumor and endothelial cells. The inhibition of SOD1 leads to inhibition of endothelial cell proliferation in vitro and attenuation of angiogenesis in vivo . The inhibition of SOD1 activity in endothelial cells is dose and time dependent and leads to an increase in the steady-state levels of superoxide anions, resulting in the inhibition of extracellular signal-regulated kinase phosphorylation without apparent induction of apoptosis. In contrast, the inhibition of SOD1 in tumor cells leads to the induction of apoptosis. The effects of ATN-224 on endothelial and tumor cells could be substantially reversed using Mn(III)tetrakis(4-benzoic acid)porphyrin chloride, a catalytic small-molecule SOD mimetic. Conclusions: These data provide a distinct molecular target for the activity of ATN-224 and provide validation for SOD1 as a target for the inhibition of angiogenesis and tumor growth.

The midpoint method for parallelization of particle simulations.

Abstract: The evaluation of interactions between nearby particles constitutes the majority of the computational workload involved in classical molecular dynamics (MD) simulations. In this paper, we introduce a new method for the parallelization of range-limited particle interactions that proves particularly suitable to MD applications. Because it applies not only to pairwise interactions but also to interactions involving three or more particles, the method can be used for evaluation of both nonbonded and bonded forces in a MD simulation. It requires less interprocessor data transfer than traditional spatial decomposition methods at all but the lowest levels of parallelism. It gains an additional practical advantage in certain commonly used interprocessor communication networks by distributing the communication burden more evenly across network links and by decreasing the associated latency. When used to parallelize MD, it further reduces communication requirements by allowing the computations associated with short-range nonbonded interactions, long-range electrostatics, bonded interactions, and particle migration to use much of the same communicated data. We also introduce certain variants of this method that can significantly improve the balance of computational load across processors.

Synthesis and evaluation of multisubstrate bicyclic pyrimidine nucleoside inhibitors of human thymidine phosphorylase.

Abstract: A series of novel, multisubstrate, bicyclic pyrimidine nucleoside inhibitors of human thymidine phosphorylase (TP) is described. Thymidine phosphorylase has been implicated in angiogenesis and plays a significant role in tumor progression and metastasis. The presence and orientation of the phosphonate moiety (acting as a phosphate mimic) in these derivatives were critical for inhibitory activity. The most active compounds possessed a phosphonate group in an endo orientation. This was consistent with molecular modeling results that showed the endo isomer protein-ligand complex to be lower in energy than the exo complex.

Theory and modeling of ion acceleration from the interaction of ultra-intense lasers with solid density targets

Abstract: The interaction of a high intensity, short-pulse laser with a thin target can lead to the generation of a highly collimated beam of fast ions off the rear target surface. These ion beams have the potential to impact inertial confinement fusion applications, including their use in diagnostics and fast-ignition. Recent work by the authors in the modeling of ion acceleration, using both full particle-in-cell and hybrid (particle ions, reduced electron physics) models, is leading to improved understanding of the physics governing ion acceleration.

Scalable method for the evaluation of distance-limited pairwise particle interactions

Abstract: A generalized approach to particle interaction can confer advantages over previously described method in terms of one or more of communications bandwidth and latency and memory access characteristics. These generalizations can involve one or more of at least spatial decomposition, import region rounding, and multiple zone communication scheduling. In a parallel implementation, the generalized approach can have the advantage that the communication bandwidth required by several instances of the approach come close or achieve an approximate lower bound for communication bandwidth. In a serial processing implementation, effective cache utilization can substantially reduce memory latency in processing.

Parallel computer architecture for computation of particle interactions

Abstract: A computation system for computing interactions in a multiple-body simulation includes an array of processing modules arranged into one or more serially interconnected processing groups of the processing modules. Each of the processing modules includes storage for data elements and includes circuitry for performing pairwise computations between data elements each associated with a spatial location. Each of the pairwise computations makes use of a data element from the storage of the processing module and a data element passing through the serially interconnected processing modules. Each of the processing modules includes circuitry for selecting the pairs of data elements according to separations between spatial locations associated with the data elements.