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Anton: A Special-Purpose Machine for Molecular Dynamics Simulation
- in Proc. 34th International Symposium on Computer Architecture (ISCA’07
, 2007
"... The ability to perform long, accurate molecular dynamics (MD) simulations involving proteins and other biological macromolecules could in principle provide answers to some of the most important currently outstanding questions in the fields of biology, chemistry and medicine. A wide range of biologic ..."
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Cited by 65 (8 self)
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The ability to perform long, accurate molecular dynamics (MD) simulations involving proteins and other biological macromolecules could in principle provide answers to some of the most important currently outstanding questions in the fields of biology, chemistry and medicine. A wide range of biologically interesting phenomena, however, occur over time scales on the order of a millisecond—about three orders of magnitude beyond the duration of the longest current MD simulations. In this paper, we describe a massively parallel machine called Anton, which should be capable of executing millisecondscale classical MD simulations of such biomolecular systems. The machine, which is scheduled for completion by the end of 2008, is based on 512 identical MD-specific ASICs that interact in a tightly coupled manner using a specialized high-speed communication
Adapting a Message-Driven Parallel Application to GPU-Accelerated Clusters
- in International Conference on High Performance Computing, Networking, Storage and Analysis, 2008. SC 2008
, 2008
"... ‡ The authors contributed equally. § To whom correspondence should be addressed. Abstract—Graphics processing units (GPUs) have become an attractive option for accelerating scientific computations as a result of advances in the performance and flexibility of GPU hardware, and due to the availability ..."
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Cited by 46 (5 self)
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‡ The authors contributed equally. § To whom correspondence should be addressed. Abstract—Graphics processing units (GPUs) have become an attractive option for accelerating scientific computations as a result of advances in the performance and flexibility of GPU hardware, and due to the availability of GPU software development tools targeting general purpose and scientific computation. However, effective use of GPUs in clusters presents a number of application development and system integration challenges. We describe strategies for the decomposition and scheduling of computation among CPU cores and GPUs, and techniques for overlapping communication and CPU computation with GPU kernel execution. We report the adaptation of these techniques to NAMD, a widely-used parallel molecular dynamics simulation package, and present performance results for a 64-core 64-GPU cluster. I.
Drug discovery using chemical systems biology: identification of the protein-ligand binding network to explain the side effects of CETP Inhibitors. PLoS Comput Biol 2009; 5: e1000387
"... Nelfinavir is a potent HIV-protease inhibitor with pleiotropic effects in cancer cells. Experimental studies connect its anti-cancer effects to the suppression of the Akt signaling pathway, but the actual molecular targets remain unknown. Using a structural proteome-wide off-target pipeline, which i ..."
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Cited by 45 (4 self)
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Nelfinavir is a potent HIV-protease inhibitor with pleiotropic effects in cancer cells. Experimental studies connect its anti-cancer effects to the suppression of the Akt signaling pathway, but the actual molecular targets remain unknown. Using a structural proteome-wide off-target pipeline, which integrates molecular dynamics simulation and MM/GBSA free energy calculations with ligand binding site comparison and biological network analysis, we identified putative human off-targets of Nelfinavir and analyzed the impact on the associated biological processes. Our results suggest that Nelfinavir is able to inhibit multiple members of the protein kinase-like superfamily, which are involved in the regulation of cellular processes vital for carcinogenesis and metastasis. The computational predictions are supported by kinase activity assays and are consistent with existing experimental and clinical evidence. This finding provides a molecular basis to explain the broad-spectrum anti-cancer effect of Nelfinavir and presents opportunities to optimize the drug as a targeted polypharmacology agent.
Virtual Machine Aware Communication Libraries for High Performance Computing
"... As the size and complexity of modern computing systems keep increasing to meet the demanding requirements of High Performance Computing (HPC) applications, manageability is becoming a critical concern to achieve both high performance and high productivity computing. Meanwhile, virtual machine (VM) t ..."
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Cited by 39 (2 self)
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As the size and complexity of modern computing systems keep increasing to meet the demanding requirements of High Performance Computing (HPC) applications, manageability is becoming a critical concern to achieve both high performance and high productivity computing. Meanwhile, virtual machine (VM) technologies have become popular in both industry and academia due to various features designed to ease system management and administration. While a VM-based environment can greatly help manageability on large-scale computing systems, concerns over performance have largely blocked the HPC community from embracing VM technologies. In this paper, we follow three steps to demonstrate the ability to achieve near-native performance in a VM-based environment for HPC. First, we propose Inter-VM Communication
COTSon: Infrastructure For Full System Simulation
- Operating Systems Review
, 2009
"... Simulation has historically been the primary technique used for evaluating the performance of new proposals in computer architecture. Speed and complexity considerations have traditionally limited its applicability to single-thread processors running application-level code. This is no longer suffici ..."
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Cited by 36 (2 self)
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Simulation has historically been the primary technique used for evaluating the performance of new proposals in computer architecture. Speed and complexity considerations have traditionally limited its applicability to single-thread processors running application-level code. This is no longer sufficient to model modern multicore systems running the complex workloads of commercial interest today. COTSon is a simulator framework jointly developed by HP Labs and AMD. The goal of COTSon is to provide fast and accurate evaluation of current and future computing systems, covering the full software stack and complete hardware models. It targets cluster-level systems composed of hundreds of commodity multicore nodes and their associated devices connected through a standard communication network. COTSon adopts a functional-directed philosophy, where fast functional emulators and timing models cooperate to improve the simulation accuracy at a speed sufficient to simulate the full stack of applications, middleware and OSs. This paper describes the changes in simulation philosophy we embraced in COTSon to address these new challenges. We base functional emulation on established, fast and validated tools that support commodity OSs and complex multitier applications. Through a robust interface between the functional and timing domain, we can leverage other existing simulators for individual sub-components, such as disks or networks. We abandon the idea of “always-on ” cyclebased simulation in favor of statistical sampling approaches that can trade accuracy for speed. COTSon opens up a new dimension in the speed/accuracy space, allowing simulation of a cluster of nodes several orders of magnitude faster with a minimal accuracy loss.
Ion conduction through MscS as determined by electrophysiology and simulation
, 2007
"... ABSTRACT The mechanosensitive channel of small conductance (MscS) is a membrane protein thought to act as a safety valve in bacteria, regulating the release of ions and small solutes when gated by membrane tension under challenging osmotic conditions. The influence of voltage on channel activation a ..."
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Cited by 26 (5 self)
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ABSTRACT The mechanosensitive channel of small conductance (MscS) is a membrane protein thought to act as a safety valve in bacteria, regulating the release of ions and small solutes when gated by membrane tension under challenging osmotic conditions. The influence of voltage on channel activation and the functional state depicted by the available crystal structure of MscS remain debated. Therefore, in an effort to relate electrophysiological measurements on MscS and properties of the MscS crystal conformation, we report here MscS’s response to voltage and pressure as determined by patch-clamp experiments, as well as MscS electrostatics and transport properties as determined through all-atom molecular dynamics simulations of the protein embedded in a lipid bilayer, a 224,000-atom system. The experiments reveal that MscS is a slightly anion-selective channel with a conductance of;1 ns, activated by pressure and inactivated in a voltage-dependent manner. On the other hand, the simulations, covering over 200 ns and including biasing electrostatic potentials, show that MscS restrained to the crystal conformation exhibits low conductance; unrestrained it increases the channel radius upon application of a large electrostatic bias and exhibits then ion conduction that matches experimentally determined conductances. The simulated conductance stems mainly from Cl ÿ ions.
A scalable fpga-based multiprocessor
- In Proceedings of the 13th Annual IEEE Symposium on FieldProgrammable Custom Computing Machines
, 2006
"... It has been shown that a small number of FPGAs can significantly accelerate certain computing tasks by up to two or three orders of magnitude. However, particularly intensive large-scale computing applications, such as molecular dynamics simulations of biological systems, underscore the need for eve ..."
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Cited by 22 (4 self)
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It has been shown that a small number of FPGAs can significantly accelerate certain computing tasks by up to two or three orders of magnitude. However, particularly intensive large-scale computing applications, such as molecular dynamics simulations of biological systems, underscore the need for even greater speedups to address relevant length and time scales. In this work, we propose an architecture for a scalable computing machine built entirely using FPGA computing nodes. The machine enables designers to implement largescale computing applications using a heterogeneous combination of hardware accelerators and embedded microprocessors spread across many FPGAs, all interconnected by a flexible communication network. Parallelism at multiple levels of granularity within an application can be exploited to obtain the maximum computational throughput. By focusing on applications that exhibit a high computation-tocommunication ratio, we narrow the extent of this investigation to the development of a suitable communication infrastructure for our machine, as well as an appropriate programming model and design flow for implementing applications. By providing a simple, abstracted communication interface with the objective of being able to scale to thousands of FPGA nodes, the proposed architecture appears to the programmer as a unified, extensible FPGA fabric. A programming model based on the MPI message-passing standard is also presented as a means for partitioning an application into independent computing tasks that can be implemented on our architecture. Finally, we demonstrate the first use of our design flow by developing a simple molecular dynamics simulation application for the proposed machine, which runs on a small platform of development boards. 1.
Four-Scale Description of Membrane Sculpting by BAR Domains
"... ABSTRACT BAR domains are proteins that sense and sculpt curved membranes in cells, furnishing a relatively well-studied example of mechanisms employed in cellular morphogenesis. We report a computational study of membrane bending by BAR domains at four levels of resolution, described by 1), all-atom ..."
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Cited by 22 (5 self)
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ABSTRACT BAR domains are proteins that sense and sculpt curved membranes in cells, furnishing a relatively well-studied example of mechanisms employed in cellular morphogenesis. We report a computational study of membrane bending by BAR domains at four levels of resolution, described by 1), all-atom molecular dynamics; 2), residue-based coarse-graining (resolving single amino acids and lipid molecules); 3), shape-based coarse-graining (resolving overall protein and membrane shapes); and 4), a continuum elastic membrane model. Membrane sculpting performed by BAR domains collectively is observed in agreement with experiments. Different arrangements of BAR domains on the membrane surface are found to lead to distinct membrane curvatures and bending dynamics.
Molecular Dynamics Simulations and Drug Discovery
- BMC Biol
"... This review discusses the many roles atomistic computer simulations of macromolecular (for example, protein) receptors and their associated small-molecule ligands can play in drug discovery, including the identification of cryptic or allosteric binding sites, the enhancement of traditional virtualsc ..."
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Cited by 21 (1 self)
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This review discusses the many roles atomistic computer simulations of macromolecular (for example, protein) receptors and their associated small-molecule ligands can play in drug discovery, including the identification of cryptic or allosteric binding sites, the enhancement of traditional virtualscreening methodologies, and the direct prediction of small-molecule binding energies. The limitations of current simulation methodologies, including the high computational costs and approximations of molecular forces required, are also discussed. With constant improvements in both computer power and algorithm design, the future of computer-aided drug design is promising; molecular dynamics simulations are likely to play an increasingly important role. Keywords molecular dynamics simulations, computeraided drug discovery, cryptic binding sites, allosteric binding sites, virtual screening, free-energy prediction.}
