HOW ARE CLOSE RESIDUES OF PROTEIN STRUCTURES DISTRIBUTED IN PRIMARY SEQUENCE

Structurally neighboring residues are categorized according to their s eparation in the primary sequence as proximal (1-4 positions apart) an d otherwise distal, which in turn is divided into near (5-20 positions ), far (21-50 positions), very far (>50 positions), and interchain (fr om different chains of the same structure), These categories describe the linear distance histogram (LDH) for three-dimensional neighboring residue types. Among the main results are the following: (i) Nearest-n eighbor hydrophobic residues tend to be increasingly distally separate d in the linear sequence, thus most often connecting distinct secondar y structure units, (ii) The LDHs of oppositely charged nearest-neighbo rs emphasize proximal positions with a subsidiary maximum for very far positions. (iii) Cysteine-cysteine structural interactions rarely inv olve proximal positions, (iv) The greatest numbers of interchain speci fic nearest-neighbors in protein structures are composed of oppositely charged residues. (v) The largest fraction of side-chain neighboring residues from beta-strands involves near positions, emphasizing associ ations between consecutive strands, (vi) Exposed residue pairs are pre dominantly located in proximal linear positions, while buried residue pairs principally correspond to far or very far distal positions. The results are principally invariant to protein sizes, amino acid usages, linear distance normalizations, and over- and underrepresentations am ong nearest-neighbor types, Interpretations and hypotheses concerning the LDHs, particularly those of hydrophobic and charged pairings, are discussed with respect to protein stability and functionality, The pro nounced occurrence of oppositely charged interchain contacts is consis tent with many observations on protein complexes where multichain stab ilization is facilitated by electrostatic interactions.