Locating Multiple Transition Pathways for Complex Biomolecules.

Area of Science:

• Computational Chemistry
• Biophysics
• Molecular Dynamics

Background:

• Locating low free energy paths (LFEPs) is crucial for understanding biomolecular functional dynamics.
• Existing methods like Traveling-Salesman-based Automated Path Searching (TAPS) efficiently find single paths but struggle with multiple parallel pathways.

Purpose of the Study:

• To develop and demonstrate a comprehensive protocol for efficiently sampling multiple parallel LFEPs in complex biomolecules.
• To reveal novel mechanistic insights into biomolecular conformational changes by identifying diverse transition pathways.

Main Methods:

• A modified parallel cascade approach was used to generate numerous distinct paths in implicit solvents.
• Paths were clustered and filtered by cumulative barriers.
• Optimized initial paths were refined using TAPS in explicit solvents.

Main Results:

• Successfully sampled eight LFEPs for Met-enkephalin's 310-helix to β-turn transition.
• Identified four LFEPs for the L99A variant of T4 Lysozyme (T4L-L99A).
• Discovered novel mechanistic insights from two previously unreported T4L-L99A transition paths.

Conclusions:

• The developed protocol is robust and efficient for sampling multiple transition paths in complex biomolecular conformational changes.
• This method provides a powerful tool for uncovering the full spectrum of functional dynamics in biomolecules.