a–d, Distances between CGRP and CLR residues relevant to key hydrogen bonds. The x axis denotes sampling time for the 16 merged molecular dynamics replicas of the whole system (each replica is separated by a vertical dashed line). a, Distance between the peptide Asp3 carboxylic carbon and receptor R3556.59 guanidinium carbon. b, Distance between the peptide Thr6 side-chain oxygen atom and the receptor H2955.40 side-chain nitrogen atoms (for each frame, the closest nitrogen to Thr6 was considered). c, Distance between the peptide Arg11 guanidinium carbon and the receptor D3667.39 carboxylic carbon. d, Distance between peptide Arg18 guanidinium carbon and receptor D287ECL2 carboxylic carbon. In most cases, the distances corresponding to hydrogen-bond formation are slightly longer than the standard 2.8 Å. e, Hydrogen bonds between CGRP and CLR during molecular dynamics simulations (6.4 μs). The total persistence of a residue side chain is plotted onto the experimental structure according to a rainbow colour scale, with residues that are never involved in blue and residues that are highly involved in red. The peptide (italics, dashed line) is depicted as thin ribbon, whereas the receptor (solid line) is shown as bulky ribbon. Key side chains are shown, but for intermittent hydrogen bonds, the rotameric state has been modified to show an interaction. Residues forming an interaction network are labelled with the same colour. Bottom, hydrogen bonds between the CGRP N terminus and the transmembrane bundle of CLR. Top, hydrogen bonds between the CGRP C terminus and the ECD of CLR; quantitative data on the persistence of hydrogen bonds during the simulations are reported in Supplementary Table 3. f, Contacts between CGRP and CLR–RAMP1 during molecular dynamics simulations (6.4 μs). The total persistence of a residue side chain is plotted onto the experimental structure according to a cyan–maroon colour scale, with residues that are never involved in cyan and residues that are highly involved in maroon. The peptide (italics, dashed line) is depicted as a thin ribbon, while the receptor (solid line) is shown as a bulky ribbon and transparent surface. Left, contacts between the N terminus of CGRP and the transmembrane bundle of the CLR: highly persistent hydrophobic interactions characterize peptide residues Leu12, Leu16, His10 and receptor residues L1952.68, A1381.36 and H2955.40. Right, contacts between the C terminus of CGRP and the ECD of CLR; highly persistent contacts characterize peptide residues Val32, Thr30, Phe37 and receptor residues Q93ECD and W72ECD. RAMP1 residues F83R, W84R are mainly engaged by CGRP residue Phe37.