Protein design under competition for amino acids availability

Abstract

Understanding the origin of the 20 letter alphabet of proteins is a long-lasting biophysical problem. In particular, studies focused extensively on the effect of a reduced alphabet size on the folding properties. However, the natural alphabet is a compromise between versatility and optimisation of the available resources.Here, for the first time, we include the additional impact of the relative availability of the amino acids. We present a protein design scheme that involves the competition for resources between a protein and a potential interaction partner that, additionally, gives us the chance to investigate the effect of the reduced alphabet on protein-protein interactions. We identify the optimal reduced set of letters for the design of the protein, and we observe that even alphabets reduced down to 4 letters allow for single protein folding. However, it is only with 6 letters that we achieve optimal folding, thus recovering experimental observations.Additionally, we notice that the binding between the protein and a potential interaction partner could not be avoided with the investigated reduced alphabets. Therefore, we suggest that aggregation could have been a driving force for the evolution of the large protein alphabet.

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“…On the other hand, to reduce the binding strength, few random residues on the non-binding region of the proteinreceptor complex can be forced to be hydrophilic, setting the balance between the folded-bound and the unfolded-unbound state. Although this scheme has extensively been tested only on lattice proteins, a preliminary study using the Caterpillar model seems to confirm that the same working principle applies in the continuum 313 . In fact, the preliminary results obtained so far with this model show that it is possible to design proteins so that they bind specifically to pockets tailored to the ligand native structure (see Figure 6).…”

“…3mx7). 330 The turquoise surface covering the protein (colored yellow) is made of a mesh of hard particles (colored orange) with the radius equal to the hard core radius of the Caterpillar model (2 Å). When the protein is pushed into the mesh, the hard particles are repelled by the self-avoiding interaction.…”

“…The binding affinity of the designed proteins can be controlled in the same way as for lattice proteins, i.e., by using the randomness of the artificial sequence. 313 . The turquoise surface covering the protein (colored in yellow) is made of a mesh of hard particles (colored in orange) with the radius equal to the hard core radius of the Caterpillar model (2 Å).…”

“…Although this scheme has been extensively tested only on lattice proteins, a preliminary study using the Caterpillar model seems to confirm that the same working principle applies in the continuum. 330 In fact, the preliminary results obtained so far with this model show that it is possible to design proteins so that they bind specifically to pockets tailored to the ligand native structure (see Fig. 7).…”

“…Fig.6Schematic representation of an ideal pocket designed to reproduce the structure of the human Fas apoptotic inhibitory protein (PDB Id. 3mx7)313 . The turquoise surface covering the protein (colored in yellow) is made of a mesh of hard particles (colored in orange) with the radius equal to the hard core radius of the Caterpillar model (2 Å).…”