Shrestha, U. R. | Search bioRxiv

bioRxiv2020

Full structural ensembles of intrinsically disordered proteins from unbiased molecular dynamics simulations

Molecular dynamics (MD) simulation is widely used to complement ensemble-averaged experiments of intrinsically disordered proteins (IDPs). However, MD often suffers from limitations of inaccuracy in the force fields and inadequate sampling. Here, we show that enhancing the sampling using Hamiltonian replica-exchange MD led to unbiased ensembles of unprecedented accuracy, reproducing small-angle scattering and NMR chemical shift experiments, for three IDPs of variable sequence properties using two recently optimized force fields. Surprisingly, we reveal that despite differences in their sequence, the inter-chain statistics of all three IDPs are similar for short contour lengths (< 10 residues).

biophysics↗

bioRxiv2020

Mesophilic enzyme function at high temperature: moleculardynamics of hyperthermophilic and mesophilicpyrophosphatases

The mesophilic inorganic pyrophosphatase from Escherichia coli (EcPPase) retains function at 353 K, the physiological temperature of hyperthermophilic Thermoccoccus thioreducens, whereas, the homolog protein from the hyperthermophilic organism (TtPPase) cannot function at room temperature. To explain this asymmetric behavior, we examined structural and dynamical properties of the two proteins using molecular dynamics simulations. The global flexibility of TtPPase is significantly higher than its mesophilic homolog at all tested temperature/pressure conditions. However, at 353 K, EcPPase reduces its solvent-exposed surface area and increases subunit compaction while maintaining flexibility in its catalytic pocket. In contrast, TtPPase lacks this adaptability and has increased rigidity and reduced protein:water interactions in its catalytic pocket at room temperature, providing a plausible explanation for its inactivity near room temperature.

biophysics↗