Sequence-Dependent Conformational Transitions of Disordered Proteins During Condensation

Area of Science:

• Biochemistry
• Biophysics
• Computational Biology

Background:

• Intrinsically disordered proteins (IDPs) form biomolecular condensates via phase separation, crucial for cellular functions.
• Protein conformation within these condensates, including dilute, dense, and interface phases, dictates functionality.
• Understanding IDP conformational dynamics during condensation is essential but remains challenging.

Approach:

• Utilized a coarse-grained polyampholyte model with tunable sequences (alternating to block-like glutamic acid and lysine).
• Performed simulations at varying concentrations to observe phase transitions and conformational changes.
• Validated findings against naturally occurring proteins involved in condensate formation.

Key Points:

• Sequence patterns dictate dilute phase conformations, ranging from ideal-like to semi-compact.
• Dense phase chain conformation is approximately ideal, independent of the initial protein sequence.
• Chains assemble via oligomeric clusters, with individual chains swelling during condensation.
• Interface chains exhibit sequence dependence and are more collapsed than bulk dense phase chains.

Conclusions:

• Protein sequence critically influences IDP behavior in dilute phases and at condensate interfaces.
• Dense phase IDP conformation is less sensitive to sequence, suggesting a universal collapse mechanism.
• This work provides insights into sequence-structure-function relationships in IDP condensates.