Molecular dynamics simulations of the intrinsically disordered protein amelogenin

Abstract

Amelogenin refers to a class of intrinsically disordered proteins that are the major constituents of enamel matrix derivative (EMD), an extract of porcine fetal teeth used in regenerative periodontal therapy. Modifications in molecular conformation induced by external stresses, such as changes in temperature or pH, are known to reduce the effectiveness of EMD. However, detailed descriptions of the conformational behavior of native amelogenin are lacking in the open literature. In the present work, a molecular model for the secondary and tertiary structure of the full-length major porcine amelogenin P173 was constructed from its primary sequence by replica exchange molecular dynamics (REMD) simulations. The REMD results for isolated amelogenin molecules at different temperatures were shown to be consistent with the available spectroscopic data. They therefore represent an important first step toward the simulation of the intra- and intermolecular interactions that mediate self-organization in amelogenin and its behavior in the presence of other EMD components under conditions representative of its therapeutic application.

Oxidation‐induced destabilization of the fibrinogen αC‐domain dimer investigated by molecular dynamics simulations

“…A similar study with the dimer would be computationally prohibitive because an even larger number of replicas would be required for temperature swaps to occur. In this study, the GBSA implicit solvation model was used to reduce the number of atoms and replicas . To test whether GBSA is a suitable approximation, 300 K simulations were performed with human α C domain using GBSA and were compared to the explicit solvent simulations.…”

“…Here, we used T‐REMD to explore the free energy landscape (FEL) of the α C‐domain dimer in the unoxidized state and compare it to the FEL in the oxidized state. The GBSA implicit solvation model was used to decrease the number of atoms, thus requiring fewer replicas. The simulations consisted of eight replicas with the following temperatures: 300.0, 306.30, 312.74, 319.31, 326.02, 332.87, 339.86, and 347.00 K. This set of temperatures was obtained using the temperature generator for REMD simulations available online through http://folding.bmc.uu.se/remd/ indicating a desired swapping frequency of 0.45 .…”

“…30 Here, we used T-REMD to explore the free energy landscape (FEL) of the αC-domain dimer in the unoxidized state and compare it to the FEL in the oxidized state. The GBSA implicit solvation model 19,20,27 was used to decrease the number of atoms, thus requiring fewer rep- 31 After every 10 ps, temperatures between adjacent replicas were swapped according to a Metropolis criterion. 30,31 After running the simulations, the achieved swapping frequencies were 0.43 ± 0.04 for the unoxidized simulations and 0.40 ± 0.01 for the oxidized simulations.…”

“…476 The goal was to understand how Met 476 contributes to the formation of the dimer and how conversion to methionine sulfoxide impairs its function. In order to improve sampling efficiency, the T‐REMD simulations were performed using an implicit solvent model . The obtained models of the α C‐domain dimers were tested and further analyzed through simulations in explicit solvent.…”

“…In order to improve sampling efficiency, the T-REMD simulations were performed using an implicit solvent model. 19,20 The obtained models of the αC-domain dimers were tested and further analyzed through simulations in explicit solvent.…”