Large-scale computer simulations help understand SARS

A Mayo Clinic researcher is the first to develop a series of three-dimensional (3D) models of an enzyme responsible for the replication of the deadly SARS (Severe Acute Respiratory syndrome) virus.

These instantaneous “structures-in-time” are central to designing an anti-SARS drug -- and are therefore a welcome advance as the virus continues to threaten public health.

The structure and dynamics of the SARS viral enzyme, called chymotrypsin-like cysteine proteinase, is described in the online version of the journal Proteins: Structure, Function, and Bioinformatics. Mayo Clinic researcher Yuan-Ping Pang, Ph.D., a chemist and head of the Computer-Aided Molecular Design Laboratory, reports results produced by the terascale computer he designed, built and managed. Using 800 PC processors harnessed together, Dr. Pang analyzed the SARS viral genome and built, atom by atom, the instantaneous 3D structures of the viral enzyme -- each of which is composed of 8,113 atoms -- just 20 days after the SARS viral genome was made public.

By performing exceptionally large-scale computer simulations, which his powerful computer system is capable of performing, Dr. Pang was able to quickly and correctly convert a genomic sequence into the 3D structures of a protein that encodes the blueprint for an anti-SARS drug. This ability is crucial in digesting the information available from the emerging fields of genomics and proteomics and in combating emerging infectious diseases. This work also demonstrates the successful use of low-cost, “homemade” computers for large-scale simulations of biological systems.

Since the SARS outbreak emerged in early 2003, international researchers raced to obtain the 3D structure of the key SARS viral enzyme so drug design could progress. To date, three independent X-ray crystallography groups have decoded the 3D structures, which are expressed as atomic coordinates. Dr. Pang deposited computer-derived coordinates of his 3D instantaneous structures to the Protein Data Bank on April 30, 2003, and released these structures to the public on July 2, 2003 -- 27 days before the release of the first X-ray structure.

Now that he knows the attributes of the SARS viral enzyme, Dr. Pang uses his customized computers to assess a Mayo in-house chemicals database -- a kind of “dictionary of small molecules” -- that his team built. It contains attributes such as molecular weight, shape and polarity of 2.5 million unique chemical structures. His goal is to match their properties with the computer-revealed dynamic properties of the key SARS viral enzyme -- and by so doing, discover an anti-SARS drug. He is also pushing toward faster computer systems, aiming at petaflops speed -- that’s one thousand trillion floating-point operations per second.

Dr. Pang and Andrea Dooley, a summer undergraduate student from Massachusetts Institute of Technology, have finished this search at Mayo and just sent 20 computer-identified small molecules to Southern Research Institute in Birmingham, Ala. for further testing as anti-SARS drugs.

http://www.mayoclinic.com/