Loop-driven conformational transition between the alternative and collapsed form of prethrombin-2: targeted molecular...

Area of Science:

• Biochemistry and structural biology
• Protein conformational dynamics
• Molecular modeling and simulation

Background:

• Prethrombin-2 exists in distinct alternative and collapsed crystal structures.
• Understanding the transition between these states is key to protein function.

Purpose of the Study:

• To elucidate the conformational transition mechanism of prethrombin-2 from its alternative to collapsed form.
• To identify key residues and structural elements involved in this transition.

Main Methods:

• X-ray crystallography to determine distinct prethrombin-2 structures.
• Targeted molecular dynamics (TMD) simulations to analyze conformational changes.
• Analysis of hydrophobic residue movements and loop region control.

Main Results:

• Identified significant conformational differences in specific hydrophobic residues (W60d, W148, W215, F227) between the two structures.
• TMD simulations revealed a concerted movement of these residues through dimer, trimer, and tetramer states during the transition.
• Discovered that specific loop regions control the concerted movement of hydrophobic residues.

Conclusions:

• Proposed a sequential scenario for the alternative to collapsed conformational transition of prethrombin-2.
• Highlighted the critical role of coordinated hydrophobic residue and loop region dynamics in protein structural changes.
• Mutant W148A simulation provided partial support for the proposed transition mechanism.