Inverse protein folding problem: designing polymer sequences.

Abstract

We consider the question of how to design proteins. How can we find "good" amino acid sequences (D) that fold to a desired "target" structure as a native conformation of lowest accessible free energy and (ii) that will not simultaneously fold to many other conformations of the same free energy? Current protein designs often focus on helix propensities and turns. We focus here on designing the hydrophobicity. For a model of self-avoiding hydrophobic/polar chains on two-dimensional square lattices, geometric proofs and exhaustive enumerations show the following results. (i) The strategy hydrophobic residues inside/polar residues outside is not optimal. Placement of additional hydrophobic residues on the surface is often necessary. (u) To avoid unwanted conformations, the designed sequence must have neither too many nor too few hydrophobic residues. (iii) The computational complexity of inverse folding appears to be in a different class than folding: unlike the folding problem, the design problem does not scale exponentially with chain length. Some design strategies, described here for the lattice model, produce good sequences and scale only linearly with chain length.Recently there have been major advances in protein design [i.e., in the design of amino acid sequences that will fold to desired "target" native conformations (1-11)]. However, the following several hurdles remain to be overcome. (i) So far, most designed proteins have only simple symmetries-4-helix bundles and all-sheet conformations, for example (2-4, 9, 10).(ii) Most of the "rational" aspects of design currently focus on the interactions among the "connected" neighbors [i.e., on the intrinsic propensities of monomeric and dimeric amino acids to form helices and turns (12-16)]. However, major forces of folding are due to hydrophobic and other "nonlocal" interactions [i.e., among monomers far apart in the sequence (17-19)]. The main design principle currently used for them is hydrophobic (H) residues inside/polar (P) residues outside. Nevertheless, many real proteins have exposed nonpolar and buried polar units (20,21), and some single-site mutations contradict the hydrophobic residues inside/pol~ar residues outside principle (22). Are there more subtle principles that are important? (iii) A major design problem has been how to avoid simultaneous folding to wrong conformations; designed sequences sometimes appear to fold to "gemiche" states, involving multiple or wrong native structures (ref. 4 and T. Handel, personal communication). It is not known how to control the multiplicity of stable structures (i.e., how to design the desired structure uniquely into the sequence). The problem of sequence design is the "inverse protein folding" problem (23)(24)(25). Whereas the input of a protein folding algorithm would be an amino acid sequence and the output would be a native structure, the input for an inverse folding algorithm would be a desired native structure and the output would be a sequence that will fold to it. Can heuristic rules be f...

Biophysics of protein evolution and evolutionary protein biophysics

“…This requirement is conceptually similar to the well-known principle for protein design, i.e. that an optimized sequence has to 'design in' the target structure as well as 'design out' alternative structures [111]. Many natural proteins have evolved not only to fold to the functional native state but also to strongly destabilize non-native intermediate states [112] by increasing the energetic separation between the folded and unfolded states [113,114] such that the folding-unfolding transition is switch-like [36,115].…”

Ribosome‐mediated translational pause and protein domain organization

“…Similarly, the four preferred polar but uncharged residues (Cys, Ser, Thr, and Tyr) showed a reduced surface accessibility, as was also the case with the preferred charged residue His. These results could suggest that the residues forming the slow regions are not essential for the final domain structure in proteins because they are unlikely, for example, to act as particularly buried hydrophobic nucleation centers or as greatly exposed polar residues maintaining solvent association to aid the folding process (Bowie & Sauer, 1989;Bowie et al, 1990;Yue & Dill, 1992;Kamtekar et al, 1993). As a result, they can remain in the ribosome channel and thus indirectly foster a translational pause that directly aids domain folding.…”

A polymetamorphic protein

“…28 Protein folding is driven in large part by hydrophobic association, and protein sequences generally require a threshold level of hydrophobicity to fold stably into a compact structure, [29][30][31][32] but simple protein models suggest that excessively hydrophobic sequences are less likely to fold uniquely. 28,[33][34][35] High or increased hydrophobicity is experimentally associated with chameleon sequences, lowered structural specificity, or outright fold changes in a number of proteins. 15,18,[36][37][38] Effects can range from increased dynamics and loss of tertiary specificity without a clear change in fold, 36,37 to native state aggregation, 39 to variations in tertiary folding topology, 15 to nonnative aggregation including amyloidogenesis.…”