Temperature-induced collapse of a disordered peptide observed by three sampling methods in molecular dynamics...

Area of Science:

• Computational chemistry and biophysics
• Molecular dynamics simulations
• Protein structure and dynamics

Background:

• Intrinsically disordered proteins (IDPs) lack stable tertiary structures, posing challenges for traditional simulation methods.
• Understanding the conformational ensembles of IDPs is crucial for elucidating their function.
• Enhanced sampling techniques are needed to overcome energy barriers and explore diverse conformational states.

Purpose of the Study:

• To compare the efficiency and accuracy of conventional molecular dynamics (cMD), temperature replica exchange (TREMD), and replica exchange with solute tempering (REST) for sampling IDP conformational ensembles.
• To identify the optimal simulation method for studying the temperature-dependent behavior of disordered peptides.

Main Methods:

• Simulated polyglutamine Q15, a model disordered peptide, across a wide temperature range.
• Employed multiple replicates of cMD, TREMD, and REST simulations.
• Analyzed conformational ensembles using radius of gyration, asphericity, secondary structure, and hydrogen bonding patterns.

Main Results:

• All three methods captured progressive collapse of the peptide at higher temperatures.
• cMD, despite extensive simulation time (90 μs), missed a high-α-helical subspace accessible by TREMD and REST.
• REST (36 μs) required less simulation time than TREMD (42 μs) to achieve comparable sampling, with REST expected to be significantly more efficient for larger IDPs.

Conclusions:

• REST is the most efficient and effective method for conformational sampling of intrinsically disordered proteins.
• Enhanced sampling techniques like REST are essential for fully characterizing the complex conformational landscapes of IDPs.