Amino acid alphabet reduction preserves fold information contained in contact interactions in proteins

Abstract

To reduce complexity, understand generalized rules of protein folding, and facilitate de novo protein design, the 20-letter amino acid alphabet is commonly reduced to a smaller alphabet by clustering amino acids based on some measure of similarity. In this work, we seek the optimal alphabet that preserves as much of the structural information found in long-range (contact) interactions among amino acids in natively-folded proteins. We employ the Information Maximization Device, based on information theory, to partition the amino acids into well-defined clusters. Numbering from 2 to 19 groups, these optimal clusters of amino acids, while generated automatically, embody well-known properties of amino acids such as hydrophobicity/polarity, charge, size, and aromaticity, and are demonstrated to maintain the discriminative power of long-range interactions with minimal loss of mutual information. Our measurements suggest that reduced alphabets (of less than 10) are able to capture virtually all of the information residing in native contacts and may be sufficient for fold recognition, as demonstrated by extensive threading tests. In an expansive survey of the literature, we observe that alphabets derived from various approaches-including those derived from physicochemical intuition, local structure considerations, and sequence alignments of remote homologs-fare consistently well in preserving contact interaction information, highlighting a convergence in the various factors thought to be relevant to the folding code. Moreover, we find that alphabets commonly used in experimental protein design are nearly optimal and are largely coherent with observations that have arisen in this work.

Improved metagenomic analysis with Kraken 2

“…To perform translated search, Kraken 2X first builds a database from a set of reference proteins in the same manner that Kraken 2 does for nucleotide sequences. The usual alphabet of 20 amino acids is reduced to 15 using the 15-character alphabet of Solis 31 ; we add a single additional value representing selenocysteine, pyrrolysine, and translation termination (stop codons). This gives us 16 characters in our reduced alphabet, allowing us to represent a character with 4 bits.…”

“…For Kraken 2, we performed two parameter sweeps, with one focused on minimizer-based subsampling, and one focused on hash-based subsampling. The first parameter sweep looked at values for ℓ in the interval [25,31], values for k in the interval [ℓ, ℓ+10], and values for s in the interval [0, 7]; the second parameter sweep looked at values of ℓ in the interval [25,31], fixed k= ℓ, values for f in the set {0.125, 0.25, 0.5}, and values for s in the interval [0,7]. We also performed a third parameter sweep, focused on translated search (Kraken 2X), where we looked at values for ℓ in the interval [11,15], values for k in the interval [ℓ, ℓ+3], and values for s in the interval [0, 3].…”

Simplification of complexity in protein molecular systems by grouping amino acids: a view from physics

“…This idea is implicitly included in other simplifications. Practically, the sequence-structure mapping could be described with information gains comparing to the random sequence [103], the ability of family recognition [104], as well as the mutual information based on contact population [105], and so on. Due to the complexity of the concerned data, some optimization methods are employed to search the optimal groupings which Figure 5.…”

“…Similarities are observed for the groupings with various methods. [105,115] Meanwhile, together with the simplifications, some features may not be correctly described after simplifications. For example, experiments and simulations suggest that the HP grouping could not describe all the features of natural proteins [92,95] though it is a common feature of proteins.…”

“…While further considering the dynamic and functional behaviors, 8-10 groups of amino acids would be necessary [50,79,90,92,93,102,[119][120][121]. Together with all these considerations, the minimal set to fulfill various kinds of biological functions might be the alphabet with 10 amino acids, which are verified with sequence design and homolog recognition [79,93,102,105,110,122]. This measures the possible complexity of protein systems.…”