Do Natural Proteins Differ from Random Sequences Polypeptides? Natural vs. Random Proteins Classification Using an Evolutionary Neural Network

Are extant proteins the exquisite result of natural selection or are they random sequences slightly edited by evolution? This question has puzzled biochemists for long time and several groups have addressed this issue comparing natural protein sequences to completely random ones coming to contradicting conclusions. Previous works in literature focused on the analysis of primary structure in an attempt to identify possible signature of evolutionary editing. Conversely, in this work we compare a set of 762 natural proteins with an average length of 70 amino acids and an equal number of completely random ones of comparable length on the basis of their structural features. We use an ad hoc Evolutionary Neural Network Algorithm (ENNA) in order to assess whether and to what extent natural proteins are edited from random polypeptides employing 11 different structure-related variables (i.e. net charge, volume, surface area, coil, alpha helix, beta sheet, percentage of coil, percentage of alpha helix, percentage of beta sheet, percentage of secondary structure and surface hydrophobicity). The ENNA algorithm is capable to correctly distinguish natural proteins from random ones with an accuracy of 94.36%. Furthermore, we study the structural features of 32 random polypeptides misclassified as natural ones to unveil any structural similarity to natural proteins. Results show that random proteins misclassified by the ENNA algorithm exhibit a significant fold similarity to portions or subdomains of extant proteins at atomic resolution. Altogether, our results suggest that natural proteins are significantly edited from random polypeptides and evolutionary editing can be readily detected analyzing structural features. Furthermore, we also show that the ENNA, employing simple structural descriptors, can predict whether a protein chain is natural or random.