Owing to the special nature of their roles in life processes, biological macromolecules such as proteins, nucleic acids, and carbohydrates have evolved into systems exhibiting a high degree of structu ral diversity and complexity. Theoretical/computational chemistry bears the responsibility of predicting, characterizing, and explaining the biological reasons for the three-dimensional shapes or "structures" adopted by tho se macromolecules. However, researchers should be aware (particularly on first entering this problem area) that the concept of "structure" has multiple interpretations that depend on the physical and chemical circumstances involved . As explained in the main text, prediction of the preferred structure adopted by any given molecule is usually reduced in principle, if not in practice, to the study of minima on a suitable energy surface in a multidimensional space of configurational coordinates. In many--but not all--cases, the global minimum corresponds to the biologically active structure, while higher-lying relative minima correspond to inactive denatured forms. The figure below shows, in simple cartoon fashion, three generic energy surfaces. The simplest (a) contains but a single minimum that would be easy to locate numerically. The next (b) shows multiple minima and requires more effort if a full classificatio n of extrema is warranted by the problem it represents. Case (c) is most representative of the situation with biological macromolecules, with a vast array of minima arranged in basins or valleys over a wide range of length scales. In this last circumstance, the concept of "structure" depends in part on the level of accuracy that is warranted, and that level is strongly dependent on temperature. At very low temperature (e.g., a protein frozen in its aqueous medium), thermally e xcited vibrations will be so feeble that the system of protein and water molecules would be trapped in the vicinity of a single fine-grained minimum. Raising the temperature stimulates transitions between neighboring microbasins, so the relevan t notion of "structure" entails the average configuration for the broadened distribution. A simple view would be that raising the temperature effectively smooths out the finer features of the complicated energy surface. This amou nts to passage from (c) to (b) in the figure.
In the vicinity of room temperature, where the aqueous medium is liquid, it is traditional to average over the solvent degrees of freedom and to utilize the resulting "free energy surface" for biological macromolecule studies. Consequently, the configuration space undergoes a reduction in dimensionality to that of just the macromolecule's flexible degrees of freedom. At the same time, the surface to be searched for minima becomes temperature dependent, so the number of minima it exhibits, whe re they are located, and indeed which is the absolute minimum can vary. Furthermore, interbasin transitions can produce substantial configurational fluctuations even in this reduced-dimensionality representation, requiring a correspo ndingly permissive definition of "structure
NAS Home Page | NAP Home Page | Reading Room | MCTCC Home Page