Optimization of Conformational Dynamics in an Epistatic Evolutionary Trajectory.

Area of Science:

• Biochemistry
• Molecular Biology
• Evolutionary Biology

Background:

• Protein evolution links molecular traits to organismal fitness.
• Biological activity and robustness are key evolutionary factors.
• Conformational dynamics' role in protein evolution is understudied.

Purpose of the Study:

• Investigate the role of conformational dynamics in protein evolution.
• Analyze dynamic features of a metallo-β-lactamase and its variants.
• Determine if conformational dynamics is an evolvable trait.

Main Methods:

• Utilized Nuclear Magnetic Resonance (NMR) spectroscopy.
• Studied protein dynamics at atomic resolution in solution.
• Analyzed a wild-type metallo-β-lactamase and three directed evolution variants.

Main Results:

• Conformational dynamics on the microsecond to millisecond timescale is optimized during evolution.
• Mutation effects on dynamics exhibit epistasis, impacting the bacterial phenotype.
• Specific mutations (Gly262Ser, Asn70Ser) alter dynamics around the active site.

Conclusions:

• Conformational dynamics is an evolvable trait in proteins.
• Optimized dynamics correlate with evolutionary trajectories.
• Proteins with dynamic active sites have greater evolutionary potential.