Evolutionary Conserved Positions Define Protein Conformational Diversity.

Area of Science:

• Biophysics
• Structural Biology
• Computational Biology

Background:

• Protein function is modulated by the conformational diversity of its native state.
• Ligand binding shifts conformational equilibrium towards higher-affinity states.
• Intramolecular vibrational dynamics drive conformational transitions, potentially linked to evolutionary conservation.

Purpose of the Study:

• To develop a novel computational method for identifying key residues involved in ligand-binding-induced conformational diversity.
• To investigate the relationship between normal modes, conformational changes, and evolutionary conservation in proteins.

Main Methods:

• Utilized normal mode analysis on a coarse-grained protein model.
• Analyzed a dataset of 188 paired protein structures (bound and unbound forms).
• Simulated point mutations to assess their impact on normal mode subspaces related to conformational changes.

Main Results:

• Identified key positions that, when mutated, significantly alter normal mode subspaces associated with ligand binding.
• Found a negative correlation between the impact of mutations on these subspaces and evolutionary conservation at specific positions.
• Key positions are evolutionarily conserved, often buried aliphatic residues in regular secondary structures (β-sheets, α-helices).

Conclusions:

• The developed method successfully identifies dynamically important residues mediating ligand-binding conformational changes.
• Evolutionary conservation patterns reflect the functional importance of these dynamically critical residues.
• These findings provide insights into protein adaptation and the structural underpinnings of ligand-protein interactions.