Structures of N‐termini of helices in proteins

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Abstract
We have surveyed 393 N‐termini of α‐helices and 156 N‐termini of 310‐helices in 85 high resolution, non‐homologous protein crystal structures for N‐cap side‐chain rotamer preferences, hydrogen bonding patterns, and solvent accessibilities. We find very strong rotamer preferences that are unique to N‐cap sites. The following rules are generally observed for N‐capping in α‐helices: Thr and Ser N‐cap side chains adopt the gauche— rotamer, hydrogen bond to the N3 NH and have Ψ restricted to 164 ± 8°. Asp and Asn N‐cap side chains either adopt the gauche— rotamer and hydrogen bond to the N3 NH with Ψ = 172 ± 10°, or adopt the trans rotamer and hydrogen bond to both the N2 and N3 NH groups with Ψ = 107 ± 19°. With all other N‐caps, the side chain is found in the gauche + rotamer so that the side chain does not interact unfavorably with the N‐terminus by blocking solvation and Ψ is unrestricted. An i, i + 3 hydrogen bond from N3 NH to the N‐cap backbone C=O in more likely to form at the N‐terminus when an unfavorable N‐cap is present. In the 310‐helix Asn and Asp remain favorable N‐caps as they can hydrogen bond to the N2 NH while in the trans rotamer; in contrast, Ser and Thr are disfavored as their preferred hydrogen bonding partner (N3 NH) is inaccessible. This suggests that Ser is the optimum choice of N‐cap when α‐helix formation is to be encouraged while 310‐helix formation discouraged. The strong energetic and structural preferences found for N‐caps, which differ greatly from positions within helix interiors, suggest that N‐caps should be treated explicitly in any consideration of helical structure in peptides or proteins.
Funding Information
  • BBSRC (BI02CT-92524)
  • BBSRC (U.K.) studentship