Preferred left-handed conformations of glycyls with pathogenic variants protect against aggregation

Due to the lack of C{beta} atom, the glycyl residues can exhibit left-handed Ramachandran conformations that are mostly disallowed for L-amino acids. The structural and functional significance of distinct glycyl conformations remains under-appreciated. Through systematic analyses of various datasets, we show that: i) the left-handed glycyl residues are over-represented at disease-associated sites and are evolutionarily conserved. ii) The mutations of L-disallowed Gly tend to destabilize the native folding as assessed through the change in free energies. An independent analysis of folding nuclei further corroborates the findings. iii) L-disallowed Gly are enriched at the aggregation gatekeepers, more significantly so in thermophiles, and the mutations thereof reduce the protein solubility. (iv) The positive{Phi} dihedral angle of L-disallowed Gly disorients its C atom out of the phase of alternating pleats of {beta}-strand, conforming a crescent that is incompatible to further pair with other {beta}-strands, and thus discourages the inter-molecular aggregation of {beta}-strands during protein folding. v) L-disallowed conformation of Gly holds predictive power to identify sites having pathogenic variants. Altogether, our observations highlight that the L-disallowed conformations of glycyls are evolutionarily selected to endow protein stability and protection against aggregation. Apart from enhancing the existing knowledge, the findings have implications in prioritizing the genetic lesions implicated in diseases, and in designing proteins with greater stability and solubility.