As in any challenging science problem, a sensible approach is to consider the hints provided by nature. In spite of their diversity, globular proteins share some amazing commonalities: they fold rapidly and reproduc-ibly (Anfinsen, 1973); their folding is driven by the affinity or lack of certain side chains and the backbone to the surrounding water; they are able to catalyze reactions and speed them up by many orders of magnitude; the folded forms of proteins are comprised of helices and sheets - the scaffolding which is provided by hydrogen bonds (Pauling & Corey, 1951; Pauling, Corey, & Branson, 1951); and proteins seem to have a generic propensity to aggregate and form amyloid (Dobson, 2003), which, in turn, is implicated in debilitating diseases. A remarkable experimental observation is that the total number of distinct folds seems to be of the order of just a few thousand (Chothia & Finkelstein, 1990). More than 70 years ago, Bernal wrote a remarkable paper entitled, "Structure of Proteins" (Bernal, 1939), whose abstract reads: The structure of proteins is the major unsolved problem on the boundary of chemistry and biology to-day. We have not yet found the key to the problem, but in recent years a mass of new evidence and new lines of attack have enabled us to see it in a far more concrete and precise form, and to have some hope that we are near to solving it. Bernal goes on to suggest: Any effective picture of protein structure must provide at the same time for the common character of all proteins as exemplified by their many chemical and physical similarities, and for the highly specific nature of each protein type.
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