  Globular proteins undergo thermal fluctuations in solution, while maintaining
an overall well-defined folded structure. In particular, studies have shown
that the core structure of globular proteins differs in small, but significant
ways when they are solved by x-ray crystallography versus solution-based NMR
spectroscopy. Given these discrepancies, it is unclear whether molecular
dynamics (MD) simulations can accurately recapitulate protein conformations. We
therefore perform extensive MD simulations across multiple force fields and
sampling techniques to investigate the degree to which computer simulations can
capture the ensemble of conformations observed in experiments. By analyzing
fluctuations in the atomic coordinates and core packing, we show that
conformations sampled in MD simulations both move away from and sample a larger
conformational space than the ensemble of structures observed in NMR
experiments. However, we find that adding inter-residue distance restraints
that match those obtained via Nuclear Overhauser Effect measurements enables
the MD simulations to sample more NMR-like conformations, though significant
differences between the core packing features in restrained MD and the NMR
ensemble remain. Given that the protein structures obtained from the MD
simulations possess smaller and less dense protein cores compared to those
solved by NMR, we suggest that future improvements to MD forcefields should aim
to increase the packing of hydrophobic residues in protein cores.
