Sampling of Protein Folding Transitions: Multicanonical Versus Replica Exchange Molecular Dynamics

Area of Science:

• Computational biology
• Biophysics
• Protein dynamics

Background:

• Molecular dynamics (MD) simulations are crucial for understanding protein folding.
• Efficiently sampling folding/unfolding events remains a challenge in MD.
• Enhanced sampling techniques aim to overcome timescale limitations in simulations.

Purpose of the Study:

• To compare the efficiency of multicanonical (MU MD) and replica exchange molecular dynamics (RE MD) for sampling protein folding/unfolding events.
• To apply an efficient sampling method to study the folding landscape of a specific protein.

Main Methods:

• Simulations using a Go-model for the 75-residue MNK6 protein to compare MU MD and RE MD.
• All-atom simulations with an implicit solvent model for the 36-residue DS119 protein using enhanced sampling.
• Analysis of folding/unfolding events and intermediate structures.

Main Results:

• MU MD demonstrated a 30-fold improvement in sampling folding/unfolding events compared to RE MD in Go-model simulations.
• The folding landscape of DS119 revealed that central helix formation is the rate-limiting step.
• The central helix acts as a scaffold for the parallel beta-sheet formation at the chain ends.

Conclusions:

• Multicanonical molecular dynamics is a more efficient enhanced sampling technique than replica exchange for protein folding simulations.
• The folding pathway of DS119 involves initial helix formation followed by beta-sheet assembly.
• These findings provide insights into protein folding mechanisms and the utility of advanced simulation methods.