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

Abstract

The conformational ensembles of a disordered peptide, polyglutamine Q15, over a wide temperature range were sampled using multiple replicates of conventional molecular dynamics (cMD) simulations as well as two enhanced sampling methods, temperature replica exchange (TREMD) and replica exchange with solute tempering (REST). The radius of gyration, asphericity, secondary structure, and hydrogen bonding patterns were used for the comparison of the sampling methods. Overall, the three sampling methods generated similar conformational ensembles, with progressive collapse at higher temperatures. Although accumulating the longest simulation time (90 s), cMD at room temperature missed a small subspace that was sampled by both TREMD and REST. This subspace was high in α-helical content and separated from the main conformational space by an energy barrier. REST used less simulation time than TREMD (36s versus 42 s), and this gap is expected to widen significantly for larger disordered proteins. We conclude that REST is the method of choice for conformational sampling of intrinsically disordered proteins.

Albumin Alters the Conformational Ensemble of Amyloid-β by Promiscuous Interactions: Implications for Amyloid Inhibition

“…Our study demonstrates that the REST2 method is suitable for studying IDPs, as other studies have done ( Pang and Zhou, 2015 ; Rossetti et al, 2016 ; Smith et al, 2016 ; Han et al, 2017 ; Lee and Chen, 2017 ; Hicks and Zhou, 2018 ). More intriguingly, we present an example of using it to achieve efficient sampling of the IDP-protein complex, given that simulations of such systems are generally resource demanding.…”

“…As an alternative, the replica exchange with solute tempering (REST) method has been developed ( Liu et al, 2005 ) and later modified in REST2 ( Wang et al, 2011 ) to improve sampling efficiency. It has been successfully applied to the conformational sampling of IDPs ( Côté et al, 2015 ; Rossetti et al, 2016 ; Smith et al, 2016 ; Han et al, 2017 ; Lee and Chen, 2017 ; Hicks and Zhou, 2018 ). REST2 is a new form of Hamiltonian replica exchange method wherein all replicas are simulated at the same temperature T 0 albeit on different deformed potential energy surfaces.…”

Atomistic Modeling of Intrinsically Disordered Proteins Under Polyethylene Glycol Crowding: Quantitative Comparison with Experimental Data and Implication of Protein–Crowder Attraction

“…While R g provides a good measure for the size of an IDP, the asphericity provides a very useful measure on the shape of the IDP. 31, 49–50 The latter is defined as δ=1−3λ12λ22+λ12λ32+λ22λ32(λ12+λ22+λ32)2 where λ 1,2,3 are the eigenvalues of the moment of inertia tensor. The value of δ ranges from 0 to 1, with 0 representing a sphere and 1 representing a thin rod.…”

Thermodynamically driven assemblies and liquid–liquid phase separations in biology

“…An interesting phenomenon that has been recently studied using molecular simulations is the collapse of some unfolded peptides-including some IDPs-upon increasing temperature [208][209][210]. This behavior is in contrast to the tendency of most polymers to swell upon heating [211], and has been attributed to temperaturedependent per-residue hydration energies for such peptides [212][213][214]. For instance, Wuttke et al [212] investigate chain compaction in five proteins that can exist in an unfolded state under physiologically relevant conditions using FRET experiments, theory and molecular simulations.…”