Protein design experiments have shown that the use of specific subsets of amino acids can produce foldable proteins. This prompts the question of whether there is a minimal amino acid alphabet which could be used to fold all proteins. In this work we make an analogy between sequence patterns which produce foldable sequences and those which make it possible to detect structural homologs by aligning sequences, and use it to suggest the possible size of such a reduced alphabet. We estimate that reduced alphabets containing 10-12 letters can be used to design foldable sequences for a large number of protein families. This estimate is based on the observation that there is little loss of the information necessary to pick out structural homologs in a clustered protein sequence database when a suitable reduction of the amino acid alphabet from 20 to 10 letters is made, but that this information is rapidly degraded when further reductions in the alphabet are made.

We first state simple rules which all electronegative scales must obey and apply these to Pauling's scale. Second, we investigate Pauling's bond energy−bond polarity equations and similar expressions that better reflect the additivity of energy. These relationships are then tested against many groups of molecules (including all of those previously tested by other research groups). Pauling χ is found to violate more than half of the elementary rules appropriate to χ scales. We also find that even the best form of the bond energy−bond polarity equation can only be satisfied by a very limited range of molecules and the form used by Pauling is only valid for a small number of bonds with low polarities.

The linear relationship between hydration-shell volume change and accessible surface area reflects the similar surface properties (fractional composition of nonpolar, polar and charged surface) among a diverse set of proteins. This linear relationship is found to be independent of how the solution is partitioned into solute and solvent components. The interpretation of hydration shell versus bulk water properties is found to be very model dependent, however. The maximally exposed unfolded protein model is found to be inconsistent with experimental volume changes of unfolding.

Genome sequence/structure alignment results at http://lutece.rutgers.edu/ss_fold_predictions.

Molecular dynamics simulations of alpha-lactalbumin were performed under conditions of neutral pH and low pH in order to study the acid-induced molten globule state. Through the use of experimental techniques such as NMR and CD spectroscopy, molten globules have been characterized as being compact intermediates with secondary structure similar to that of the native protein but with tertiary structure that is disordered. The detailed structure of the molten globule state is unknown, however. Through the use of computer simulations we can study the structural changes which occur upon lowering pH. The simulations presented here differ from previous unfolding simulations in two important ways: the electrostatic interactions are treated more accurately than ever before, and artificially high temperatures are not used to force the protein to unfold. Simulations of 880 psec each were run at pH 7 (control simulation) and pH 2. We concentrate on the interesting changes in the tertiary interactions within the protein with lowering of pH. In particular, there is a loss of native tertiary contacts in the beta domain and interdomain region, and a large decrease in interdomain hydrogen bonds.