Identifying a folding nucleus for the lysozyme/α-lactalbumin family from sequence conservation clusters

Four subfamilies of c-type lysozyme and one subfamily of alpha-lactalbumin are defined from 78 sequences, and their folding nucleus is identified with a method based on conserved residues and native structural contacts between pairs of conserved residues. One large cluster of 19 conserved residues is found which is mostly nonpolar, buried, and nonfunctional. It can be subdivided into three subclusters: (1) conserved residues in four helices; (2) conserved residues that stabilize the connector between the a and the beta domains; and (3) a beta-turn, sitting in the middle of a bowl of alpha-helix residues. It is proposed that this folding nucleus initiates four helices, A, B, C, and D, three beta sheets, and the connector, which corresponds closely to the nucleation of the so-called fast folding track pathway. As the secondary structures propagate, nonconserved residues and functionally conserved residues would form additional contacts. The conserved residues are selected with a phylogenetic scheme in which single members of subfamilies are selected. Subfamilies are then equally weighted to obtain the consensus conservation.