Structural and dynamical effects of targeted mutations on μO-Conotoxin MfVIA: Molecular simulation studies

Conotoxins are a group of cysteine-rich, neurotoxic peptides isolated from the venom of marine cone snails. MfVIA is a member of the μO-conotoxin family, and acts as an inhibitor of subtype 1.8 voltage-gated sodium ion channels (Na_V1.8). The unique selectivity of MfVIA as an inhibitor of Na_V1.8 makes it an ideal peptide for elucidation of the physiological functions of this voltage-gated ion channel. Previous experimental studies of point mutations of MfVIA showed that the double mutant [E5K,E8K] exhibited greater activity at Na_V1.8 relative to the wild-type toxin. The present study employs molecular dynamics (MD) simulations to examine the effects of various mutations at these key residues (E5 and E8) on the structure and dynamics of MfVIA. Five double mutants were studied, in which the positions 5 and 8 residues were mutated to amino acids with a range of different physicochemical properties, namely [E5A,E8A], [E5D,E8D], [E5F,E8F], [E5K,E8K], and [E5R,E8R]. Except for [E5D,E8D], all of the mutants tend to show decreased contacts at the N-terminus owing to the loss of the R1-E5 salt bridge relative to that of the wild-type, which subsequently lead to greater exposure and flexibility of the N-terminus for most of the mutant peptides studied, potentially rendering them more able to interact with other species, including Na_V1.8. Molecular docking studies of the peptides to Na_V1.8 via different binding mechanisms suggest that the [E5R, E8R] mutant may be especially worthy of further investigation owing to its predicted binding mode, which differs markedly from those of the other peptides in this study.