Sequence-dependent conformational transitions of disordered proteins during condensation

Area of Science:

• Biophysics
• Protein Science
• Molecular Biology

Background:

• Intrinsically disordered proteins (IDPs) undergo phase separation to form biomolecular condensates.
• Protein conformation within these condensates (dense, dilute, and interface phases) is crucial for function.
• Understanding residue-level conformational changes during condensation is challenging.

Purpose of the Study:

• To investigate sequence-dependent conformational transitions of IDPs during phase separation.
• To elucidate how sequence patterns influence IDP conformations in dilute, dense, and interface phases.
• To provide insights into the behavior of IDPs lacking secondary structures within condensates.

Main Methods:

• Utilized a coarse-grained polyampholyte model with tunable sequence patterns (alternating to block-like).
• Performed simulations across varying protein concentrations to observe phase behavior.
• Validated findings with naturally occurring protein sequences involved in condensate formation.

Main Results:

• Sequence patterns influenced dilute phase conformations from ideal-like to semi-compact.
• Dense phase conformations approached ideal chain behavior irrespective of sequence.
• Chains transitioned from oligomeric clusters to the dense phase with individual chain swelling.
• Interface conformations exhibited strong sequence dependence, being more collapsed than bulk dense phase.

Conclusions:

• IDP sequence patterns significantly govern dilute phase and interface conformations.
• Dense phase behavior shows convergence towards ideal chain characteristics.
• This work offers detailed insights into sequence-driven conformational dynamics of IDPs in biomolecular condensates.