Epilepsy Related Slack Channel Mutants Lead to Channel Over-Activity by Two Different Mechanisms

combination with a previously available variant, show folding kinetics that is in correspondence with the results obtained from autocorrelation analysis of single-trajectory full-atom molecular dynamics simulations for a similar mutant. Closer investigation of existing all-atom computational data suggests that helix 2 of lambda 6-85 is involved in a short-lived off-pathway trap, which is in agreement with experimental data. Our work demonstrates that a match between fast protein folding experiments and molecular dynamics simulations can be extended to several reaction coordinates to obtain experimental confirmation of deviations from two-state folding behavior even for very simple folding reactions. As computation becomes more affordable, it will be possible to simulate both the new probes and any mechanistic deviations that insertion of the probe causes in experiment.