X-ray crystallography and molecular dynamics are two methods that play a significant role in drug discovery efforts. We present recent advances in molecular dynamics simulations of crystals. This novel approach seeks to interface information from both methods for their mutual benefit. Results of extensive simulations of crystalline lysozyme using four different modern force fields and a collective sampling of over 100µs of the protein are reported. We show unprecedented agreement with experimental data but also limitations and possible directions for continued development of molecular dynamics. We also show how molecular dynamics of crystals can elucidate crystal heterogeneity, dynamics and solvent behavior that is often hidden in the time and space averaged diffraction data. Finally, we highlight recent efforts at integrating molecular dynamics in crystal refinement schemes for improved structural modeling of macromolecules and small ligands. These efforts advance our understanding of both methods and lead to methodological improvements in both.

Molecular dynamics of crystals

250th National Meeting (2015)

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