Protein function evolution through the lens of conformational dynamics: A single-molecule perspective

Area of Science:

• Biochemistry
• Molecular Biology
• Protein Evolution

Background:

• Classical protein evolution models focus on sequence-structure relationships.
• Emerging evidence suggests protein function arises from an ensemble of conformations encoded in the sequence.
• Conformational dynamics are increasingly recognized as crucial for protein activity, specificity, and regulation.

Purpose of the Study:

• To highlight the central role of conformational dynamics in protein evolution.
• To explore how dynamics are programmable for protein design.
• To bridge the understanding of protein function under cellular, non-equilibrium conditions.

Main Methods:

• Single-molecule Förster resonance energy transfer (smFRET) to resolve heterogeneous and transient protein conformations.
• Analysis of disordered proteins as a model for dynamics-driven evolution.
• Principles of dynamics-based protein design.

Main Results:

• Protein dynamics, not just static structures, are a substrate for evolutionary innovation.
• Disordered proteins exemplify how dynamics serve as the primary evolutionary substrate.
• Protein dynamics are both evolvable and programmable, enabling novel protein design.

Conclusions:

• Conformational dynamics are central to understanding and engineering protein evolutionary logic.
• This framework opens new avenues for studying protein adaptation to cellular, non-equilibrium environments.
• Integrating dynamics into protein science is essential for future advancements in molecular engineering.