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In general, the evolutionary rate of proteins is not primarily related to protein and amino acid functions, and factors such as protein abundance, codon usage, and the protein's T

For most proteins, multiple sequence alignments are a viable method to identify functionally and structurally important amino acids, but for most organisms, there is a subset of proteins that are unique or found in a few closely related organisms. For these proteins, it is not possible to produce sequence alignments that are useful in identifying functionally or structurally important amino acids. We have investigated the relationship between amino acid conservation and five factors (the amino acid's identity, N-terminal neighbor, C-terminal neighbor, the local hydropathy of surrounding amino acids, and the local expected net charge of the surrounding amino acids based on the primary sequence) in Escherichia coli proteins. For four of the factors examined (all but the amino acid's identity), there is a significant relationship with conservation for some of the standard 20 amino acids. Using the combination of all five factors, we show that it is possible to calculate a score based on the primary sequences of a subset of E. coli proteins that has statistically significant predictive value with respect to predicting conserved amino acids in other E. coli proteins and Saccharomyces cerevisiae proteins. As these five variables show significant relationships with conservation, we have termed them conservation factors.

Analysis of the Arabidopsis thaliana, Saccharomyces cerevisiae, Mus musculus, Escherichia coli, Bacillus subtilis, Thermoplasma acidophilum, and Sulfolobus tokodaii genomes demonstrate that many amino acid biases occur at the N- and C-termini of proteins, a statistically significant number of these biases are evolutionarily conserved, and these biases occur in amino acids beyond the first and last five amino acids. Analyses designed to shed light on the mechanism causing amino acid biases suggest that in at least some cases the bias is caused by forces acting at the nucleic acid level. It is also demonstrated that in E. coli functionally related proteins show similar biases at the N- and C-termini suggesting that the mechanisms causing the biases are complex and in some cases are related to function.