Structural Preferences Shape the Entropic Force of Disordered Protein Ensembles

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• Intrinsically disordered protein regions (IDRs) comprise over 30% of the human proteome.
• IDRs lack stable structures, existing as dynamic conformational ensembles.
• Tethering IDRs can reduce conformational entropy, generating an entropic force with physiological relevance.

Purpose of the Study:

• To investigate how IDR sequence influences the magnitude of the entropic force upon tethering.
• To explore the relationship between IDR structural preferences and entropic force generation.
• To determine if solution chemistry can modulate this entropic force.

Main Methods:

• Utilized all-atom simulations to analyze IDR ensembles.
• Quantified entropic force based on IDR structural preferences.
• Investigated the impact of solution chemistry on entropic force strength.

Main Results:

• Sequence-encoded structural preferences significantly impact entropic force magnitude.
• Compact, spherical IDR ensembles generate substantially higher entropic forces than extended ensembles.
• Modulation of entropic force strength by changes in surrounding solution chemistry was demonstrated.

Conclusions:

• The entropic force exerted by tethered IDRs is a sequence-dependent property.
• This force is environmentally tunable, offering a mechanism for biological regulation.
• Findings provide insights into the functional implications of IDR conformational dynamics.