Stability analysis of CBD3 peptide predictsA1R2 dipeptide as a suitable
target for small molecule peptidomimetics
Underlying molecular recognition is the ability of a ligand to present a
suitable structural motif for at least a few nanoseconds to efficiently
engage its receptor (Rajamani, Thiel, Vajda & Camacho, 2004). In the
far-western assay using 15-mer peptides (overlapping by 12 amino acids)
of full-length CRMP2 revealed that the highest binding to
Cav2.2 was attained by peptide ARSRLAELRGVPRGL(CBD3) (Brittain et al., 2011b). Subsequent work showed that the first
six amino acids ARSRLA were critical for binding, mutagenesis
suggested that two residues (Ala1 and
Arg4) were important for binding (Moutal et al., 2018).
To predict the recognition motif in CBD3, we performed three independent
molecular dynamics simulations (MDS) of the full peptide and of the TAT
conjugated peptide and scanned the trajectories for the most stable
dipeptide conformation (Figure 1A; see also Figure S1 ), as well
as assessed whether the corresponding side chains are blocked by
intra-peptide contacts or are exposed to solvent and free to interact
(Figure 1B ). Simulations showed thatA1R2 dipeptide, formed the most
stable solvent exposed motif, while the rest of the peptide was mostly
cluttered (Figure 1A, B ).