Fast Method for Computing Chemical Potentials and Liquid-Liquid Phase Equilibria of Macromolecular Solutions

Area of Science:

• Thermodynamics
• Computational Chemistry
• Biophysics

Background:

• Chemical potential is key for understanding molecular system equilibria.
• Previous methods for calculating chemical potential, like FMAP, used FFT for atomistic protein-crowder interactions.
• Extending these methods to macromolecular solutions is computationally challenging.

Purpose of the Study:

• To extend the FMAP method for calculating liquid-liquid phase equilibria in macromolecular solutions.
• To determine phase coexistence using the Maxwell equal-area rule.
• To demonstrate the method's efficiency and accuracy for complex systems.

Main Methods:

• Utilized the fast Fourier transform (FFT)-based method for Modeling Atomistic Protein-crowder interactions (FMAP).
• Calculated chemical potentials across various molecular densities.
• Applied the Maxwell equal-area rule to identify liquid-liquid phase coexistence.
• Benchmarked against Lennard-Jones fluids and applied to all-atom protein models.

Main Results:

• The FMAP method accurately predicts phase diagrams for Lennard-Jones fluids at significantly reduced computational cost (18% of existing methods).
• Computational speedup increases dramatically with molecular complexity, offering orders of magnitude improvement for proteins.
• Successfully determined the liquid-liquid coexistence curve for γII-crystallin at the all-atom level.

Conclusions:

• The extended FMAP method provides an accurate and computationally efficient way to determine liquid-liquid phase equilibria for macromolecular solutions.
• This approach enables the study of phase separation in complex biological mixtures like protein-protein and protein-RNA systems.
• Opens new avenues for understanding in vitro and in vivo macromolecular phase behavior.