Changes in Lysozyme Flexibility upon Mutation Are Frequent, Large and Long-Ranged

Area of Science:

• Biophysics
• Structural Biology
• Computational Biology

Background:

• Human c-type lysozyme is a key protein with implications in various biological processes.
• Understanding protein flexibility is crucial for deciphering protein function and disease mechanisms.
• Point mutations can subtly or dramatically alter protein structure and dynamics.

Purpose of the Study:

• To investigate the impact of single point mutations on human c-type lysozyme flexibility.
• To quantify changes in backbone flexibility and pairwise mechanical couplings.
• To compare mutation-induced flexibility changes in human lysozyme with its hen egg white lysozyme (HEWL) ortholog.

Main Methods:

• Utilized a Distance Constraint Model for statistical mechanical treatment of network rigidity.
• Tracked two dynamical metrics: flexibility index and cooperativity correlation.
• Analyzed changes in backbone flexibility and pairwise mechanical couplings across residue pairs.

Main Results:

• Single point mutations frequently and significantly affect lysozyme flexibility, with effects extending over long distances.
• 48% of residues showed altered backbone flexibility, and 42% of residue pairs exhibited changes in cooperativity.
• Mutation-induced flexibility changes in human lysozyme were generally larger than in HEWL, despite lower sequence identity.

Conclusions:

• Small structural perturbations from single point mutations have a pronounced effect on lysozyme flexibility.
• The β-subdomain shows increased flexibility in mutants, aligning with its role in amyloid formation.
• Compensating mutations in HEWL may reestablish specific protein properties despite sequence divergence.