Molecular Transfer Model for pH Effects on Intrinsically Disordered Proteins: Theory and Applications

Area of Science:

• Biophysics
• Computational Biology
• Protein Science

Background:

• Intrinsically disordered proteins (IDPs) lack stable 3D structures, making their conformational ensembles challenging to study.
• pH significantly influences protein behavior by altering the protonation states of amino acid residues.

Purpose of the Study:

• To develop a theoretical framework for investigating pH-induced conformational changes in IDPs.
• To provide a computational tool for analyzing IDP properties across different pH conditions.

Main Methods:

• Generalization of the molecular transfer model (MTM) to incorporate pH effects via transfer free energy calculations.
• Utilizing the semi-grand ensemble to derive an exact expression for transfer free energy.
• Developing and applying a mean-field (MF) approximation for computationally efficient analysis.
• Employing a lattice model for comparing exact and MF results on a model IDP.

Main Results:

• The sequence-specific arrangement of charged groups is a primary determinant of IDP structural properties, overriding net charge effects.
• The MF approximation shows good agreement with exact calculations for IDPs, mitigating limitations seen in globular protein studies.
• The developed method accurately captures pH-dependent conformational heterogeneity in IDPs.

Conclusions:

• The presented theoretical method offers a robust computational approach for studying pH effects on IDPs.
• This work highlights the critical role of sequence in governing IDP structure and dynamics under varying pH conditions.
• The findings pave the way for deeper insights into the functional roles of IDPs in biological systems.