Fig. 1.

Bonding between 2F5 HCDR2 D_H54 and gp41 MPER ⁶⁶⁵K (27). The contact surface of 2F5 bound to its antigenic peptide shows a strong complementarity of charge, and two CDR H2 residues, D_H56 and D_H54, interact through hydrogen bonds and salt bridges with K⁶⁶⁵ of the 2F5 core tripeptide DKW. Based on the CDR H2 substitutions in the two UAs, the following predictions can be made. First, the CDR H2 D_H54 residue in variant 1 is retained and, if positioned appropriately, could form a salt bridge with K⁶⁶⁵ of the 2F5 core DKW. However, the bulky side chain of W_H53 (from S_H53 to W_H53, red arrow) is very likely to perturb the local environment of HCDR2, through potential steric clashes with HCDR1 backbone and F_H32 side chain, and disruption of the H bond with G_H33. Second, the additional alteration of D_H54 to N_H54 in UA variant 2 HCDR2 will disrupt the salt bridge with ⁶⁶⁵K. Also, there is a potential for HCDR2 N_H54 to H bond with D_H56, which would further preclude establishing bonding with gp41 K⁶⁶⁵. Critical CDR residues are labeled in green, HCDR1 residues are labeled in blue, and gp41 MPER residues are labeled in black. gp41 MPER is shown in yellow, and 2F5 antibody backbone is shown in white.