Structural disorder originates beyond narrow stoichiometric margins of amino acids in naturally occurring folded proteins

Abstract

Rigorous analyses of Euclidean distances between non-peptide bonded residues in structures of several thousand naturally occurring folded proteins yielded a surprising “margin of life” for percentage occurrence of individual amino acids in naturally occurring folded proteins. On one hand, the concept of “margin of life”, referring to lower than expected variances in average stoichiometric occurrences of individual amino acids in folded proteins, remains unchallenged since its discovery a decade ago. On the other hand, within this past decade there has been a strong emergence of a gradual paradigm shift in biology, from sequence-structure-function in proteins to sequence-disorder-function, fuelled by discoveries on functional implications of intrinsically disordered proteins (primary sequences that do not form stable structures). Thus the applicability of “margin of life” to peptide-bonded residues in all known natural proteins, adopting stable structures vis-à-vis intrinsically disordered needs to be explored. Therefore in this work, we analyze compositions of the complete naturally occurring primary sequence space (over 560000 sequences) after dividing it into mutually exclusive subsets of structured and intrinsically disordered proteins along with a subset without any structural information. While finding that occurrence of different peptides (up to pentapeptides) is a direct consequence of the relative occurrences of their constituting residues in folded proteins, we report that structural disorder in natural proteins originates beyond the narrow stoichiometric margins of amino acids found in structured proteins.

Communicated by Ramaswamy H. Sarma

Keywords:

• Disorder
• IDPs
• peptides
• proteins
• structure
• sequence
• synthesis
• computational biology
• bioinformatics

Acknowledgements

AMC is grateful to IIT Delhi for fellowship support. The authors also thank IIT Delhi for providing access to the HPC facility. AM is grateful to Kusuma Trust (UK) for their generous funding support towards assisting him in establishing the teaching and research programs of the School of Biological Sciences (subsequently renamed as the Kusuma School of Biological Sciences) at IIT Delhi. AM is also grateful to Dept. of Biotechnology, Government of India and the National Supercomputing Mission, Government of India for their support to the Supercomputing Facility for Bioinformatics & Computational Biology at IIT Delhi.

Author contributions

AMC and ST collected the sequence data and wrote the codes for counting the number of occurrences. AM and AMC analyzed the data and prepared the figures. DG, AP and IS recollected the sequence data at different times and wrote independent codes for counting the number of occurrences to confirm whether there were any changes in the results (fortunately negligible changes in raw data and no changes in overall results were observed). AM designed the study, supervised the work and wrote the manuscript.

Disclosure statement

The authors declare no competing interests.