The first three residues at the N terminus of the a-helix are called N1, N2
and N3. We surveyed 2102 alpha-helix N termini in 298 high-resolution, non
homologous protein crystal structures for N1, N2 and N3 amino acid and side
-chain rotamer propensities and hydrogen-bonding patterns. We find strong s
tructural preferences that are unique to these sites. The rotamer distribut
ions as a function of amino acid identity and position in the helix are oft
en explained in terms of hydrogen-bonding interactions to the free N1, N2 a
nd N3 backbone NH groups. Notably, the "good N2" amino acid residues Gln, G
lu, Asp, Asn, Ser, Thr and His preferentially form i, i or i, i + 1 hydroge
n bonds to the backbone, though this is hindered by good N-caps (Asp, Asn,
Ser, Thr and Cys) that compete for these hydrogen bond donors. We find a nu
mber of specific side-chain to side-chain interactions between N1 and N2 or
between the N-cap and N2 or N3, such as Arg(N-cap) to Asp(N2). The strong
energetic and structural preferences found for N1, N2 and N3, which differ
greatly from positions within helix interiors, suggest that these sites sho
uld be treated explicitly in any consideration of helical structure in pept
ides or proteins. (C) 1999 Academic Press.