Glassy dynamics in mutant huntingtin proteins.

Area of Science:

• Computational Biology
• Neurodegenerative Diseases
• Protein Dynamics

Background:

• Huntington's disease (HD) is caused by mutations in the huntingtin (HTT) protein, specifically an expanded poly-glutamine (polyQ) region.
• The structural role of the HTT exon-1 with the polyQ region is crucial for HD progression but remains poorly understood.
• Huntingtin protein is an intrinsically disordered protein (IDP), requiring large conformational ensembles for characterization, which is challenging experimentally.

Purpose of the Study:

• To investigate the structural properties and conformational ensemble of the HTT exon-1 with the polyQ region using molecular dynamics (MD) simulations.
• To demonstrate the necessity of enhanced sampling techniques, specifically temperature replica-exchange MD (T-REMD), for studying IDPs like HTT.
• To provide insights into the dynamics and structural features of the HTT exon-1 relevant to Huntington's disease.

Main Methods:

• Performed large-scale temperature replica-exchange molecular dynamics (T-REMD) simulations on the HTT exon-1 with the polyQ region.
• Compared T-REMD simulation data with unbiased conventional MD simulations.
• Analyzed the conformational ensembles and dynamics of the protein at various temperatures.

Main Results:

• Poly-glutamine (polyQ) regions exhibit extremely sluggish and glassy dynamics at room temperature, necessitating enhanced sampling methods for relaxation.
• T-REMD simulations successfully generated a diverse ensemble of protein structures, including those with *cis*-peptide bonds in the proline-rich domain at elevated temperatures.
• The study illustrates the limitations of conventional MD and the advantages of T-REMD for capturing the conformational landscape of intrinsically disordered proteins.

Conclusions:

• Temperature replica-exchange MD (T-REMD) is essential for adequately sampling the conformational space of intrinsically disordered proteins like huntingtin.
• The findings provide valuable structural insights into the huntingtin exon-1 and its polyQ region, relevant for understanding Huntington's disease.
• This study highlights the utility of T-REMD for future investigations of huntingtin and other intrinsically disordered proteins.