TDTAC: a generalized time-dependent torsion angle correlation framework for resolving directional coordination in...

Area of Science:

• Biophysics
• Structural Biology
• Molecular Dynamics

Background:

• Proteins undergo dynamic conformational changes crucial for function.
• Traditional methods often fail to capture how dynamics propagate through large protein assemblies.
• Understanding these dynamics is key to designing targeted therapies, like PROTACs.

Purpose of the Study:

• To introduce a novel framework, Time-Dependent Torsion Angle Correlation (TDTAC), for analyzing protein dynamics.
• To quantitatively map directional, time-lagged correlations in residue-level fluctuations.
• To investigate the dynamic mechanisms underlying targeted protein degradation by PROTACs.

Main Methods:

• Developed a generalized TDTAC framework incorporating explicit time lags between residues.
• Analyzed dihedral rotations to represent residue-level fluctuations and their propagation.
• Applied TDTAC to a PROTAC (dBET70) complex with its target (BRD4) and the E3 ligase scaffold (CRL4A).

Main Results:

• TDTAC identified two dominant pathways for motion propagation in the degradation complex, originating from the DDB1-CUL4A region.
• These pathways extend towards the CRBN-BRD4 and RBX1-Ub interfaces, respectively.
• Time-lagged coordination linked local dynamics to distal catalytic sites, facilitating a ubiquitination-competent state.

Conclusions:

• TDTAC provides a physically meaningful representation of conformational dynamics and information flow in biomolecular assemblies.
• The framework reveals coordinated, time-delayed residue rearrangements essential for PROTAC-mediated protein degradation.
• TDTAC is a generalizable tool for dissecting dynamic processes in complex biological systems.