Does Replica Exchange with Solute Tempering Efficiently Sample Aβ Peptide Conformational Ensembles?

Abstract

We have applied replica exchange with solute tempering (REST) molecular dynamics to study a short fragment of the Aβ peptide, Aβ25-35, in water and a much larger system incorporating two Aβ10-40 peptides binding to the zwitterionic dimyristoylphosphatidylcholine (DMPC) bilayer. As a control, we used traditional replica exchange molecular dynamics (REMD) applied to the same systems. Our objective was to assess the practical utility of REST simulations. Taken together, our results suggest four conclusions. First, compared to REMD, the number of replicas in REST simulations can be reduced four to five times without affecting the temperature range or compromising an efficient random walk of REST replicas over temperatures. Second, although overall REST produces much fewer conformational states than REMD, there is no substantial difference in the collection of unique states for the wild-type replica in REST and REMD, especially for the system featuring Aβ peptides binding to the lipid bilayer. Third, we performed a thorough comparison of REST and REMD equilibrium conformational ensembles, including thermal averages and probability distributions. REST reproduces REMD data extremely well for the system of Aβ peptides binding to the DMPC lipid bilayer. The agreement between REST and REMD equilibrium sampling of Aβ25-35 in water is less perfect, but it improves with addition of new REST simulations. Surprisingly, REST demonstrates much better convergence for the system featuring ordered peptides binding to lipid bilayer rather than for a small unstructured peptide solvated in water. Fourth, REST delivers its full computational advantage over REMD when applied to peptides interacting with lipid bilayers. For peptides solvated in water, REST does not appear to offer computational gain but may make replica simulations practically feasible due to a lower requirement for parallel computing environments. Our study is expected to facilitate wider application of REST in biomolecular simulations.

Role of the N‐Terminal Transmembrane Helix Contacts in the Activation of FGFR3

“…At a higher “solute” temperature, the solute–solute interaction energy is weakened by a factor of , and thereby, conformational changes of a solute molecule might occur more frequently in REST2. This method reduces the number of replicas compared to the original REMD, because the number of atoms in a solute molecule is much smaller than the whole system . In gREST, we are able to select the “solute” in a more flexible manner than REST2.…”

“…In this study, we aim to explore the dimer interface of WT FGFR3 and its change upon G380R using atomic MD simulations with enhanced conformational sampling. We utilize generalized replica exchange with solute tempering (gREST), which is a modified version of REST2 . We apply a scaling in lipid‐peptide Lennard‐Jones (LJ) interaction via NBFIX to keep a good balance of the intermolecular interactions in membrane protein simulations .…”

Structural Analysis of (p)ppGpp Reveals Its Versatile Binding Pattern for Diverse Types of Target Proteins

“…However, classical MD simulations studies on small molecules such as free nucleotides are challenging due to the presence of high energy barriers of the glycosidic bond between nucleotide base and ribose sugar as well as conformational flexibility of ribose moiety (Wang et al, 2017;Wang and Berne, 2018;Yang et al, 2019). To overcome the sampling issue, the replica-exchange method has been explored previously on small biomolecules to enhance sampling to cover more conformation space (Smith et al, 2016;Wang and Berne, 2018). Recently, cyclic nucleotides and small nucleic acid have been characterized for structural dynamics using REMD enhanced sampling methods (Šponer et al, 2014;Wang et al, 2017;Mlýnský and Bussi, 2018).…”

High resolution ensemble description of metamorphic and intrinsically disordered proteins using an efficient hybrid parallel tempering scheme

“…The approach reduced the required number of replicas by multiple folds. Such a powerful design of the Hamiltonian has been successfully shown to simulate weak binding of Aβ peptide on a lipid bilayer, 20 lateral equilibration of lipids in a bilayer 21 , and a 90-residue long SH4 unique domain protein. 22 While a much wider applications in protein folding is envisioned, however, the method underperforms in proteins where the conformations are separated by large free energy barriers producing poor mixing of replicas between the high temperature regime and low temperature regime.…”