Protein design under competing conditions for the availability of amino acids

Abstract

isolating the properties of proteins that allow them to convert sequence into the structure is a longlasting 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 impact of the relative availability of the amino acids to extract from the 20 letters the core necessary for protein stability. We present a computational 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 devise a scheme that automatically identifies 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 in the evolution of the large protein alphabet. The amino acid alphabet encoding the protein function is common to all living organisms and is the result of millions of years of evolution. It is composed of 20 letters, in contrast to the ones of other biopolymers, such as DNA and RNA, which possess 4 letters only. Such a large alphabet gives to proteins the vast variety of configurations and functions that we know so far. The advent of computational protein evolution (also known as protein design) 1-16 opens the possibility to address fundamental questions about the nature of the amino acid alphabet 17-20. Protein design consists in searching for protein sequences capable of folding into a given backbone conformation. The search is usually done by point mutations while keeping the backbone structure fixed. In addition to several applications to medicine 12,14,21-23 and material science 15,24-27 , protein design offers the possibility to explore fundamental problems of protein evolution. One of the questions that mostly attracts the attention of the scientific community is about the universality of the 20 letters. Of course, the complex spectrum of proteins functionalities calls for a wide range of building blocks. However, could it be possible to design proteins to fold using a reduced alphabet? And, if yes, why not simply stick with such a reduced alphabet? The early work on protein design with alphabets of different sizes was carried out for protein lattice models in which the protein chain is constrained to be on a cubic lattice. With such models it was possible to design heteropolymers with a large variety of alphabets defined by the amino acid interactions 28-37. It became rapidly apparent th...

Key aspects of the past 30 years of protein design

“…It is again confirming the importance of directional interactions. Proteins are a particular case of the two-patches scenario, and we confirmed the prediction of the phase diagram in figure 4 in a recent publication [180]. The study of the The line represents the alphabet size q = e ω at which the transition between not designable and designable occurs.…”

“…where the polymer designed with the indicated alphabet has been tested to fold into the target structure, while the crosses the ones where it does not (not designable) [179]. For two directional interactions, like in proteins, the minimum alphabet size for design is predicted to four letters, a prediction that has been verified computationally [180]. [176] origin of the 20-amino acid alphabet is a fascinating problem that has been extensively studied in the past 30 years.…”

CLIP-Seq analysis enables the design of protective ribosomal RNA bait oligonucleotides against C9ORF72 ALS/FTD poly-GR pathophysiology

“…Several computational studies have demonstrated that sequences of 60 or less amino acids are sufficient for modeling the full conformational space of simple repetitive sequences (55,56). It is noteworthy that the DPR proteins are unlikely to form a well-defined tertiary structure since at least four distinct amino acids are required for peptide sequences to attain a specific tertiary disposition (57,58). Thus, our findings support the notion that C9-HRE toxicity is threshold dependent and does not strongly correlate with repeat size (59)(60)(61)(62)(63).…”

CLIP-Seq Analysis Enables the Design of Ribosomal RNA Bait Oligonucleotides That Protect AgainstC9ORF72ALS/FTD-Associated Poly-GR Pathophysiology

“…Several computational studies have demonstrated that sequences of 60 or less amino acids are sufficient for modelling the full conformational space of simple repetitive sequences (Cossio et al, 2010; Zamuner et al, 2015). It is noteworthy that the DPR proteins are unlikely to form a well-defined tertiary structure since at least four distinct amino acids are required for peptide sequences to attain a specific tertiary disposition (Cardelli et al, 2019; Nerattini et al, 2020). Thus, our findings support the notion that C9-HRE toxicity is threshold dependent and does not strongly correlate with repeat size (Cammack et al, 2019; Gendron et al, 2017; Gijselinck et al, 2016; Suh et al, 2015; van Blitterswijk et al, 2013).…”