Understanding Ion Binding Affinity and Selectivity in β-Parvalbumin Using Molecular Dynamics and Mean Spherical...

Area of Science:

• Biophysics
• Computational Biology
• Protein Science

Background:

• Parvalbumin (PV) is a calcium (Ca(2+))-selective protein found in various tissues.
• Understanding the molecular basis of Ca(2+) versus magnesium (Mg(2+)) binding selectivity is crucial for protein function.

Purpose of the Study:

• To computationally investigate the molecular thermodynamics of Ca(2+) vs. Mg(2+) binding in rat β-parvalbumin (β-PV).
• To elucidate how the EF-hand scaffold influences Ca(2+) binding selectivity over Mg(2+).

Main Methods:

• Employed molecular dynamics (MD) simulations to analyze ion binding within EF-hand motifs.
• Utilized mean spherical approximation (MSA) theory to model electrolyte behavior and predict ion binding thermodynamics.
• Quantified local and global factors, including EF-hand strain and residue contacts, influencing cation selectivity.

Main Results:

• Found similar electrostatic and steric contributions for Ca(2+) and Mg(2+) binding.
• Identified a significant enthalpic difference (5.5 kcal/mol) favoring Ca(2+) when internal EF-hand strain was considered.
• Demonstrated that local factors, particularly EF-hand strain and dehydration, are primary drivers of β-PV's cation selectivity.

Conclusions:

• Internal strain within the β-PV EF hand plays a critical role in Ca(2+) selectivity over Mg(2+).
• This strain, combined with dehydration effects, likely explains the substantial difference in binding affinities reported in literature.
• The computational approach is applicable to studying metal binding thermodynamics in other EF-hand proteins.