Helix-capping motifs are specific patterns of hydrogen bonding and hydrophobic interactions found at or near the ends of helices in both proteins and peptides. In an a-helix, the first four >N-H groups and last four >C=O groups necessarily lack intrahelical hydrogen bonds. Instead, such groups are often capped by alternative hydrogen bond partners. This review enlarges our earlier hypothesis (Presta LG, Rose GD. 1988. Helix signals in proteins. Science 240:1632-1641) to include hydrophobic capping. A hydrophobic interaction that straddles the helix terminus is always associated with hydrogen-bonded capping. From a global survey among proteins of known structure, seven distinct capping motifs are identified-three at the helix N-terminus and four at the C-terminus. The consensus sequence patterns of these seven motifs, together with results from simple molecular modeling, are used to formulate useful rules of thumb for helix termination. Finally, we examine the role of helix capping as a bridge linking the conformation of secondary structure to supersecondary structure.Keywords: alpha helix; protein folding; protein secondary structure The a-helix is characterized by consecutive, main-chain, i + i -4 hydrogen bonds between each amide hydrogen and a carbonyl oxygen from the adjacent helical turn (Pauling & Corey, 1951). This pattern (Fig. 1) is interrupted at helix termini because, upon termination, no turn of helix follows to provide additional hydrogen bond partners. Such end effects are substantial, encompassing two-thirds of the residues for the protein helix of average length (Presta & Rose, 1988). Further, helix geometry hinders solvent access to amide groups in the first turn of the helix, inhibiting interaction with water and necessitating alternative hydrogen bonds. The term helix "capping" (Richardson & Richardson, 1988a) has been used to describe such alternative hydrogen bond patterns that can satisfy backbone >N -H and >C = 0 groups in the initial and final turns of the helix (Presta & Rose, 1988).Many studies involving helix capping have been conducted since publication of our initial hypothesis nine years ago (Presta & Rose, 1988). As we had proposed, amide hydrogens at the helix N-terminus are indeed satisfied predominantly by side-chain H-bond acceptors. In contrast, carbonyl oxygens at the C-terminus are satisfied primarily by backbone >N -H groups from the turn following the helix. Further, these hydrogen-bonding patterns at either helix end are accompanied by a companion hydrophobic interaction between apolar residues in the a-helix and its flanking turn. This hydrophobic component of helix capping was unanticipated.The main purpose of this review is to enlarge our previous definition of helix capping and to document the common capping motifs. Qpically, protein helices terminate in a hydrophobic interaction that straddles the helix termini (i.e., an interaction between two hydrophobic residues close in sequence, one within the helix, the other external to the helix). In this interaction,...