The solution to the protein folding problem is critical to an understanding of the naturally occurring proteins and their deliberately engineered counterparts. Our principal goal is to elucidate the stereochemical code that governs protein folding and use it to formulate a practical folding algorithm. Of particular interest is the alpha-helix, first proposed by Pauling and coworkers. Helices are a hallmark of protein structure, and much effort has been directed towards understanding which sequences can form stable helices. Two converging lines of investigation in our lab have focused separately on the central and terminal residues within the helix. For central residues, it is hypothesized that sidechain entropy is the principal factor that governs helix propensity. For terminal residues, it is hypothesized that "capping" H-bonds between sidechain polar groups and the otherwise unsatisfied initial four amide hydrogens or final four carbonyl oxygens in the mainchain are the major factor in helix specificity. Results from this work can be used predictively, and, unlike empirical strategies, such predictions are grounded in plausible thermodynamics. This work, which is well underway, will be extended to include other categories of secondary structure as well. Following the approach used for helices, residues in beta-sheet can be modelled in each microenvironment, in either middle or edge strands and at the center or terminus of the strand. Nonrepetitive structure can also be included. Preliminary results suggest that many residues have clearly understandable, sharply defined secondary structure preferences. For example, valine in the unfolded state can populate all three sidechain conformers almost equivalently, but essentially only one conformer when in a helix. The corresponding energy loss (T-delta-S) due solely to the reduction in sidechain entropy is approximately RTln3, of order physiological kT. These energy terms, which cause residues to favor one type of secondary structure over others, though individually modest, are significant in the aggregate, when summed over an entire helix or sheet. The effect of a given class of secondary structure on the sidechain entropy and/or intra-molecular hydrogen bonding of a residue is tantamount to a stereochemical code.