Mutation-induced heme pocket destabilization in myoglobinopathy

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• Myoglobin (Mb) is crucial for oxygen homeostasis and redox regulation.
• A His97Tyr mutation causes myoglobinopathy, disrupting heme interactions and leading to protein aggregation.
• Previous studies used a Lys45Arg substitution, masking the His97Tyr mutation's effects.

Purpose of the Study:

• To investigate the structural and dynamic effects of the His97Tyr mutation in myoglobin.
• To dissect the individual and combined roles of residues 45 and 97 using molecular dynamics simulations.
• To clarify the impact of sequence context on mutation-driven changes in myoglobin.

Main Methods:

• Classical molecular dynamics simulations were employed.
• Simulations compared the His97Tyr mutation in wild-type Lys45 and crystallographic Arg45 myoglobin variants.
• Analysis focused on heme pocket dynamics, residue interactions, and heme propionate redistribution.

Main Results:

• Residue 45 critically regulates long-range protein dynamics; Arg45 induces more coherent correlations than Lys45.
• Heme propionate redistribution is primarily determined by residue 45, with residue 97 having an additive effect.
• The His97Tyr mutation in the wild-type background causes heme tilting, increasing conformational flexibility.

Conclusions:

• The His97Tyr mutation alters heme dynamics and protein flexibility.
• Sequence context, particularly residue 45, is vital for understanding mutation effects on myoglobin structure and function.
• These findings provide insights into the molecular basis of myoglobinopathy.