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We use a recently developed coarse-grained computational model to investigate the relative stability of two different sets of de novo designed four–helix bundle proteins. Our simulations suggest a possible explanation for the experimentally observed increase in stability of the four–helix bundles with increasing sequence length. In details, we show that both short subsequences composed only by polar residues and additional nonpolar residues inserted, via different point mutations in ad hoc positions, seem to play a significant role in stabilizing the four–helix bundle conformation in the longer sequences. Finally, we propose an additional mutation that rescues a short amino acid sequence that would otherwise adopt a compact misfolded state. Our work suggests that simple computational models can be used as a complementary tool in the design process of de novo proteins.

We explore the question of whether local effects (originating from the amino acids intrinsic secondary structure propensities) or nonlocal effects (reflecting the sequence of amino acids as a whole) play a larger role in determining the fold of globular proteins. Earlier circular dichroism studies have shown that the pattern of polar, non polar amino acids (nonlocal effect) dominates over the amino acid intrinsic propensity (local effect) in determining the secondary structure of oligomeric peptides. In this article, we present a coarse grained computational model that allows us to quantitatively estimate the role of local and nonlocal factors in determining both the secondary and tertiary structure of small, globular proteins. The amino acid intrinsic secondary structure propensity is modeled by a dihedral potential term. This dihedral potential is parametrized to match with experimental measurements of secondary structure propensity. Similarly, the magnitude of the attraction between hydrophobic residues is parametrized to match the experimental transfer free energies of hydrophobic amino acids. Under these parametrization conditions, we systematically explore the degree of frustration a given polar, non polar pattern can tolerate when the secondary structure intrinsic propensities are in opposition to it. When the parameters are in the biophysically relevant range, we observe that the fold of small, globular proteins is determined by the pattern of polar, non polar amino acids regardless of their instrinsic secondary structure propensities. Our simulations shed new light on previous observations that tertiary interactions are more influential in determining protein structure than secondary structure propensity. The fact that this can be inferred using a simple polymer model that lacks most of the biochemical details points to the fundamental importance of binary patterning in governing folding.