10/20/2003 8:00 AM
10/21/2003 5:00 PM
Co-Chairs: John Moult and Richard Friesner
Time: October 20-21, 2003
Place: Natcher Conference Center, National Institutes of Health, Bethesda, MD
Purpose of the workshop: The purpose of this workshop is to invite experts in the field of protein structure modeling and related fields to identify the road blocks and share their visions on improving the quality of comparative models. Structural genomics is a globally fast-growing area following recent success in genome sequencing and technical breakthrough in X-ray crystallography and nuclear magnetic resonance (NMR). The U.S. effort on structural genomics is mostly supported by the NIGMS Protein Structure Initiative. High-accuracy experimentally determined 3-D structures of representatives of large protein families will be generated at an ever increasing pace. Computational structure prediction will be made using the experimental structures as templates for the other protein family members. Current technology on homology modeling can produce structural models with high success rate for backbones and intermediate to low accuracy for side chains and loops.
Participation: Experts in the fields of protein structure modeling and other biological simulation/modeling will gather to share their visionary views of how to improve the accuracy of protein structure prediction using comparative modeling approaches. A limited number of seats will be reserved for observers on a first-come-first-served basis.
Report: A long term major goal of the PSI is to produce useful models of all biological proteins, based on a representative set of experimentally determined structures. This goal recognizes that while
ab initio modeling of protein structure remains difficult, models based on homology to proteins with known structure are always possible, and the shorter the phylogenic distance between the two proteins, the higher the accuracy of the models. Modeling of this type is often termed ‘comparative’ or ‘homology’ modeling. Improvements in these modeling methods will greatly enhance the utility of PSI experimentally determined structures. In particular, obtaining models comparable in accuracy with experiment is a key objective. The goal of the workshop was to examine the current state of art in producing comparative models, to identify bottlenecks to obtaining higher accuracy, and to identify ways of moving the field forward as rapidly as possible.
The first session addressed the interplay between experimental and computational methods, with talks by Rost (Tasks for Comparative Modeling in Structural Genomics), Kim (Experimental Structures: Accuracy, Reliability, and Uses), and Moult (Strengths and Bottlenecks in Contemporary Comparative Modeling). This was followed by a session with talks from seven experts in the field (Baker, Levitt, Friesner, Honig, Sali, Dunbrack, van Gunsteren), each presenting their views on the current state of the art, bottlenecks to progress, and how these may be overcome. The third session focused on applications of comparative modeling, particularly docking and drug design (Shiochet and Peishoff), the deduction of function from structure (Skolnick), and dissemination of models (Brenner). The second day of the workshop began with a short session on modeling of membrane proteins, a currently less advanced but critical area, with talks by Weinstein and Krystek. Bob Germain then described work at IBM, primarily focused at developing very fast machines for molecular dynamics simulations.
Discussion of the talks began with ‘new ideas’ contributions from Ponder, Jacobson, Berger and Murray, highlighting central points, and adding new insight. There followed a structured discussion, aimed at determining where there is consensus in the field, and in areas of disagreement, what the range of opinion is. The main conclusions are as follows:
A first clear consensus is that comparative modeling methods are already extremely powerful. In addition to playing a central role in the PSI, the technique is of great importance in biology in general. At present, experimental structures are known for less than 1% of identified proteins, whereas relatively high quality models can be produced for 10 to 20% of proteins, and some form of model is possible for up to 60% of the proteins coded for in particular genomes. Thus the vast majority of experimentalists work with models of proteins of interest, rather than experimental structures. As more and more genomes are sequenced, reliance on models will continue to increase. In addition, models play an important part in a number of methods for obtaining structure. Two new applications described at the workshop served to illustrate this. Montelione pointed out that it is now possible to very rapidly collect substantial amounts of NMR data for proteins, and that these data could be most effectively used as restraints in generating structure models. Godzik briefly described results from a PSI center, using a set of models of proteins to significantly decrease the level of sequence similarity needed for successful use of molecular replacement methods in obtaining phases for X-ray crystal structure determination.
At the same time, it was also agreed that there is a clear need for greatly improved modeling performance, if full use is to be made of the experimental results generated by the PSI. A set of areas, activities and facilities where increased focus will result in rapid progress was identified, as follows:
For more information about the workshop, contact Jerry Li, Ph.D., at (301) 594-0828 or e-mail
Connect With Us: