Global Dynamics Renders Protein Sites with High Functional Response.

Area of Science:

• Biophysics
• Structural Biology
• Protein Engineering

Background:

• Deep mutational scanning (DMS) identifies protein positions sensitive to mutations.
• Protein function is intrinsically linked to its dynamic structural behavior.
• Understanding mutation effects is crucial for protein design and engineering.

Purpose of the Study:

• To investigate the relationship between protein structural dynamics and mutation sensitivity.
• To determine if dynamics can explain observed mutation effects identified by DMS.
• To explore the role of specific residues in mediating allosteric communication.

Main Methods:

• Utilized a dataset of seven proteins with available deep mutational scanning data.
• Employed a perturbation-response approach based on the Gaussian Network Model (GNM).
• Analyzed the correlation between mutation-sensitive sites and protein structural dynamics.

Main Results:

• Mutation-sensitive positions were found to significantly modulate global protein dynamics.
• These positions often act as intermediates for allosteric interactions within the protein structure.
• Upon perturbation, sensitive sites showed the greatest reduction in residue fluctuations, impacting function via entropy.
• This effect was notable even for sensitive positions located far from known functional regions.

Conclusions:

• Protein structural dynamics are a key determinant of mutation sensitivity.
• Mutation-sensitive residues play a critical role in allosteric regulation and communication.
• Targeting these dynamics-modulating positions offers a strategy to allosterically control protein function.