Exercises in prognostication: crystal structures and protein folding.

Abstract

G iven the molecular structure of a chemical compound, can one predict its crystal structure (1-3)? Given the amino acid sequence of a protein, can one predict its three-dimensional structure? Both questions are not only of theoretical interest but of practical interest as well. As far as the crystal structure problem is concerned, we know that polymorphic forms of the same compound may differ widely with respect to physical properties, such as melting point, vapor pressure, density, solubility, photochemical stability, etc., differences that may affect the usefulness of the compound in industrial and pharmaceutical applications. One need only think of the difference between graphite and diamond. Because the function of a protein depends on its three-dimensional conformation, the protein folding problem has obvious implications for deciphering the chemical and biological significance of the linear code expressed in the amino acid sequence. An understanding of protein folding will also help in combating misfolding diseases, e.g., Alzheimer's disease and cystic fibrosis, and even in design of proteins with new or enhanced function. The two problems, crystal structure and protein folding prediction, are very different, but they share important aspects. In particular, both problems depend on our ability to calculate the most stable arrangements of large molecular aggregates from general principles. Indeed, both challenges are usually regarded as global optimization problems to identify the structure(s) of lowest potential energy or of free energy with entropy contributions included. Both problems have been subjected to objective blind tests in which knowledge of the experimental structures was not made available to those preparing predictions until the predicted structures had been submitted to the judges. Three such crystal structure prediction tests (Crystal Structure Prediction Workshops) have been organized by Sam Motherwell and were …