Predicting substitutions to modulate disorder and stability in coiled-coils.

Area of Science:

• Computational biology
• Protein structure and dynamics
• Bioinformatics

Background:

• Coiled-coils are protein structural motifs, but can exhibit local mobility and intrinsic disorder.
• Intrinsically disordered regions are crucial for protein function but challenging to characterize.
• Quantifying disorder in protein regions computationally is an ongoing challenge.

Purpose of the Study:

• To develop a computational framework for quantifying coiled-coil disorder in solution.
• To enable the design of protein substitutions that modulate coiled-coil disorder and stability.
• To apply the framework to viral phosphoprotein multimerization domains (PMDs).

Main Methods:

• Analysis of conformational ensembles from short all-atom Molecular Dynamics (MD) simulations.
• Application to tetrameric left-handed coiled-coils of Measles virus (MeV) and Nipah virus (NiV) PMDs.
• Derivation of design rules for substitutions based on impact on coiled-coil stability.

Main Results:

• Quantified C-terminus disorder in MeV and NiV PMDs using short MD simulations.
• Established a conceptual framework for rational design of substitutions.
• Identified rules to control MeV PMD stability and cohesiveness.
• Designed substitutions to increase or decrease tetramer stability/flexibility.

Conclusions:

• The developed method serves as a platform for designing substitutions to regulate protein flexibility and stability.
• This approach aids in understanding and engineering coiled-coil behavior.
• Facilitates rational design of protein structural properties.