Folding@Home and Genome@Home: Using distributed computing to tackle previously intractable problem

For decades, researchers have been applying computer simulation to address problems in biology. However, many of these "grand challenges" in computational biology, such as simulating how proteins fold, remained unsolved due to their great complexity. Indeed, even to simulate the fastest folding protein would require decades on the fastest modern CPUs. Here, we review novel methods to fundamentally speed such previously intractable problems using a new computational paradigm: distributed computing. By efficiently harnessing tens of thousands of computers throughout the world, we have been able to break previous computational barriers. However, distributed computing brings new challenges, such as how to efficiently divide a complex calculation of many PCs that are connected by relatively slow networking. Moreover, even if the challenge of accurately reproducing reality can be conquered, a new challenge emerges: how can we take the results of these simulations (typically tens to hundreds of gigabytes of raw data) and gain some insight into the questions at hand. This challenge of the analysis of the sea of data resulting from large-scale simulation will likely remain for decades to come.

[1]  V. Pande,et al.  Pathways for protein folding: is a new view needed? , 1998, Current opinion in structural biology.

[2]  H. C. Andersen Rattle: A “velocity” version of the shake algorithm for molecular dynamics calculations , 1983 .

[3]  Michael R. Shirts,et al.  COMPUTING: Screen Savers of the World Unite! , 2000, Science.

[4]  R. Dyer,et al.  Fast events in protein folding: helix melting and formation in a small peptide. , 1996, Biochemistry.

[5]  D. Baker,et al.  Native protein sequences are close to optimal for their structures. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[6]  A. Voter Parallel replica method for dynamics of infrequent events , 1998 .

[7]  B. Matthews,et al.  Response of a protein structure to cavity-creating mutations and its relation to the hydrophobic effect. , 1992, Science.

[8]  P. Kollman,et al.  Pathways to a protein folding intermediate observed in a 1-microsecond simulation in aqueous solution. , 1998, Science.

[9]  Christopher A. Voigt,et al.  Trading accuracy for speed: A quantitative comparison of search algorithms in protein sequence design. , 2000, Journal of molecular biology.

[10]  W. C. Still,et al.  The GB/SA Continuum Model for Solvation. A Fast Analytical Method for the Calculation of Approximate Born Radii , 1997 .

[11]  W. L. Jorgensen,et al.  The OPLS [optimized potentials for liquid simulations] potential functions for proteins, energy minimizations for crystals of cyclic peptides and crambin. , 1988, Journal of the American Chemical Society.

[12]  Andrew M Wollacott,et al.  Prediction of amino acid sequence from structure , 2000, Protein science : a publication of the Protein Society.

[13]  Gerd Folkers,et al.  Molecular Modeling and Computer Aided Drug Design 1992-1993 , 1994 .

[14]  T M Handel,et al.  Review: protein design--where we were, where we are, where we're going. , 2001, Journal of structural biology.

[15]  Vijay S. Pande,et al.  Folding pathway of a lattice model for protein folding , 1998 .

[16]  C. Pabo Molecular technology: Designing proteins and peptides , 1983, Nature.

[17]  Ivet Bahar,et al.  Transition states and the meaning of Φ-values in protein folding kinetics , 2001, Nature Structural Biology.

[18]  V S Pande,et al.  Is the molten globule a third phase of proteins? , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[19]  J. Hofrichter,et al.  Laser temperature jump study of the helix<==>coil kinetics of an alanine peptide interpreted with a 'kinetic zipper' model. , 1997, Biochemistry.

[20]  J R Desjarlais,et al.  Computer search algorithms in protein modification and design. , 1998, Current opinion in structural biology.

[21]  Ian Foster,et al.  The Grid: A New Infrastructure for 21st Century Science , 2002 .

[22]  Vijay S. Pande,et al.  How accurate must potentials be for successful modeling of protein folding , 1995, cond-mat/9510123.

[23]  S L Mayo,et al.  Coupling backbone flexibility and amino acid sequence selection in protein design , 1997, Protein science : a publication of the Protein Society.

[24]  R. Rosenfeld Nature , 2009, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[25]  Luis Serrano,et al.  Formation and stability of β-hairpin structures in polypeptides , 1998 .

[26]  L Serrano,et al.  Formation and stability of beta-hairpin structures in polypeptides. , 1998, Current opinion in structural biology.

[27]  P. S. Kim,et al.  High-resolution protein design with backbone freedom. , 1998, Science.

[28]  K. Dill,et al.  From Levinthal to pathways to funnels , 1997, Nature Structural Biology.

[29]  V Muñoz,et al.  Folding dynamics and mechanism of beta-hairpin formation. , 1997, Nature.

[30]  J R Desjarlais,et al.  Side-chain and backbone flexibility in protein core design. , 1999, Journal of molecular biology.

[31]  B. Matthews,et al.  The role of backbone flexibility in the accommodation of variants that repack the core of T4 lysozyme. , 1994, Science.

[32]  M. Levitt,et al.  De novo protein design. II. Plasticity in sequence space. , 1999, Journal of molecular biology.

[33]  V S Pande,et al.  Molecular dynamics simulations of unfolding and refolding of a beta-hairpin fragment of protein G. , 1999, Proceedings of the National Academy of Sciences of the United States of America.