Microsecond Molecular Dynamics Simulations of an Alpha-Bungarotoxin Peptide Ligand

HAPep and other short synthetic peptides are promising alternatives to anti-venoms for highly-toxic neuro-toxins like a-Bungarotoxin (α-BTX). Experimental work has demonstrated that HAPep binds to α-BTX with high affinity and resolved the static structure of the bound complex. The dynamics of HAPep, especially when not bound to α-BTX, have not yet been resolved. This work reports the achievement of extending previous 200 ns molecular dynamics simulations of HAPep in bound and unbound configurations to over 28 µs (140 times longer than previous simulations) and the subsequent analyses of these simulations. Three macroscopic states were inferred using dimensionality reduction and clustering. Transition rates and times cales between the states were modeled using a Markov State Model (MSMs). The simulations indicate the presence of a stable state with non-native hydrogen bonds that may slow down and/or complicate folding pathways for reaching the ß-hairpin structure observed in the bound complex with α-BTX.