Sali, A. and T. Blundell (1993). Comparative protein modelling by satisfaction of spatial restraints. J. Mol. Biol. 234: 779-815.

Sander, C. and R. Schneider (1991). Database of homology derived protein structures and the structural meaning of sequence alignment. Proteins 9: 56-68.

Simmerling, C., M. Lee, et al. (1998). Combining MONSSTER and LES/PME to predict protein structure from amino acid sequence: Application to the small protein CMTI-1 J. Am. Chem. Soc., submitted.

Skolnick, J., A. Kolinski, et al. (1997). MONSSTER: A method for folding globular proteins with a small number of distance restraints. J. Mol. Biol. 265: 217-241.

Stowell, M.H.B. and D.C. Rees (1995). Structure and stability of membrane proteins. Adv. Protein Chem. 46: 279-311.

Thomas, D.J., G. Cesari, et al. (1996). The prediction of protein contacts from multiple sequence alignment. Protein Eng. 11: 941-948.

Wodak, S.J. and M.J. Rooman (1993). Generating and testing protein folds. Curr. Opin. Struct. Biol. 3: 247-259.

Yang, Y.F. and W.W. Wells (1991). Identification and characterization of the functional amino acids at the active center of pig liver thioltransferase by site-directed mutagenesis. J. Biol. Chem. 266: 12759-12765.


William Winter, SUNY-ESF, Syracuse: Glycosylation has to play a major role in the final selection of a particular protein conformation in many proteins where it does occur. Are you doing anything at all to use that kind of information to make further selections once you have determined a family of possible structures?

Jeffrey Skolnick: Not yet, but we are aware of the problem. So far we have picked molecular functions that are basically self-contained by design because we did not pick the hardest case first. But you are absolutely right, glycosylation is extremely important. The problem there is that not a lot is known. Even the potentials that you should put in to describe the conformational spectrum are not well established. People are still developing these, so that field is very much in its infancy. Our view has been, yes, we recognize it is important, and especially in a biological context it is very, very important; it protects the proteins and keeps them from being chewed up, but we quite frankly wanted to consider the simplest cases first to see if the basic approaches could work—choose molecular functions or biochemical functions where it is apparently not believed to be important and then work our way up. But, yes, you are absolutely right. One day we or someone else will have to deal with that problem, but I think it is premature at this stage of the game.

David Dixon, Pacific Northwest National Laboratory: Jeff, have you looked at or have you started thinking about the fact that there is also spatial resolution within a cell, and have you looked at how you connect your proteins up into cell signaling pathways?

Jeffrey Skolnick: Yes, we have already started, at least on a very schematic level, simulating peptide insertion and protein insertion into membranes, treating the system, you know, with spatial anisotropy. You have a membrane region that could be treated at various levels of detail in the interfacial regions, bulk regions, but only on a very, very schematic level at this point. As it is, these kinds of calculations really tax any resources that we can get hold of, and we are not sure about adding additional details other than on a very simplified level. And then we are not even sure that the descriptives are sufficiently good that it would be worthwhile. I mean, we are trying to proceed on a very building-block basis: establish something that works, validate it, move on, make it more complicated, move on. My guess is the next thing we are going to do is membrane protein tertiary structure prediction, and there there are some encouraging results.

The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement