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Synthesis and Structure Determination of µ-Conotoxin PIIIA Isomers with Different Disulfide Connectivities
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Effects of Conformational Constraint on Peptide Solubility Limits
Riley J Workman1, Suresh Gorle1, B Montgomery Pettitt1
1Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, Texas 77555-0304, United States.
The Journal of Physical Chemistry. B
|November 30, 2022
Summary
Cyclic and linear GGGGG peptides undergo liquid-liquid phase separation in water. Linear peptides phase separate more robustly due to stabilizing interpeptide contacts, despite higher solubility for cyclic peptides.
Area of Science:
- Biochemistry
- Chemical Physics
- Molecular Biology
Background:
- Liquid-liquid phase separation (LLPS) is crucial for biological organization, often involving intrinsically disordered proteins.
- Understanding the solution chemistry of LLPS is vital for controlling biological systems.
Purpose of the Study:
- Investigate the impact of cyclization on the LLPS of short polyglycine (GGGGG) peptides.
- Compare the phase separation behavior of cyclic GGGGG versus linear GGGGG in aqueous solutions.
Main Methods:
- Simulated supersaturated aqueous solutions of cyclic and linear GGGGG peptides.
- Analyzed spontaneous liquid-liquid phase separation.
- Quantified differences in phase separation robustness and aqueous solubility.
- Examined interpeptide interactions (van der Waals, electrostatic) and conformational entropy changes.
Main Results:
- Both cyclic and linear GGGGG underwent spontaneous LLPS.
- Linear GGGGG exhibited more robust phase separation than cyclic GGGGG.
- Cyclic GGGGG displayed higher aqueous solubility compared to linear GGGGG.
- Van der Waals interactions were enriched in the condensed phase of linear GGGGG.
- Linear GGGGG's enhanced interaction enthalpy compensated for greater conformational entropy loss.
Conclusions:
- Interpeptide contacts, particularly van der Waals forces, stabilize the condensed phase of linear GGGGG, driving its robust LLPS.
- Cyclization reduces LLPS robustness and increases solubility by altering interaction enthalpies and entropy changes.
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