INTERCHANGES OF SPATIALLY NEIGHBORING RESIDUES IN STRUCTURALLY CONSERVED ENVIRONMENTS

The question of whether interchanges of spatially neighboring residues are coupled, or whether they change independently of each other, has been addressed repeatedly over the last few years. Utilizing a residue order-independent structural comparison tool, we investigated interch anges of spatially adjacent residue pairs in conserved 3D environments in globally dissimilar protein structures. We define spatially adjace nt pairs to be non-local neighboring residues which are in spatial con tact, though separated along the backbone, to exclude backbone effects . A dataset of unrelated structures is extensively compared, construct ing a matrix of all 400x400 interchanges of residue pairs. Our study i ndicates that (i) interchanges of residues which are spatial neighbors are indepedent of each other. With the exception of a few pairs, the pattern of interchanges of pairs of adjacent residues resembles that e xpected from interchanges of single residues. However, clustering resi dues of similar characteristics, serves to enhance secondary trends. H ence, (ii) clustering the hydrophobic, aliphatic and, separately, the aromatic, and comparing them with the charged, and the polar, indicate s that hydrophobic pairs are favorably replaced by hydrophobic, and ch arged/polar by charged/polar. The most strongly conserved are the char ged. Interestingly, the type of charge (like or opposite) plays no rol e. Interchanges between the hydrophobic and hydrophilic classes are un favorable. (iii) Clustering by volume indicates that the most highly c onserved are the (Small, Small) pairs. The least favorable are interch anges of the type (Small, Small) <---->, (Large, Large). Interchanges of the type (Large, Small) <----> (Large, Large) are less favorable th an (Large, Small) <----> (Small, Small). Compensatory interchanges of the type (Large, Small) <----> (Small, Large) are unfavorable. (iv) In spection of the trends in the interchanges of the clustered small resi dues versus clustered large rigid, and separately versus clustered lar ge flexible, illustrates clear differences. Consistently, within all h ydrophobic, large and small, the flexible aliphatic differ from the mo re rigid aromatic. The flexible aliphatic residue pairs are unfavorabl y replaced by other residue types. Furthermore, (v) the unique propert ies of the aromatics, conferred by the electronic configuration of the ir benzene rings, are transformed into clear trends. Replacements of p olar residues by aromatics, while unfavorable, are nevertheless consis tently more favorable than into aliphatics. We address these issues an d their direct implications to protein design and to fold recognition.