Molecular‐dynamics simulation methods for macromolecular crystallography. Issue 1 (30th December 2022)

• Record Type: Journal Article
• Authors: Wych, David C.; Aoto, Phillip C.; Vu, Lily; Wolff, Alexander M.; Mobley, David L.; Fraser, James S.; Taylor, Susan S.; Wall, Michael E.
• Is Part Of: Acta crystallographica. Volume 79:Issue 1(2023)
• Page Start: 50
• Page End: 65
• Publication Date: 2022-12-30
• Subjects: molecular‐dynamics simulations -- water structure -- conformational ensembles -- protein kinases; X-ray crystallography -- Periodicals; Crystallography -- Periodicals; Molecular biology -- Periodicals; Molecular structure -- Periodicals; Biomolecules -- Structure -- Periodicals; Cytology -- Periodicals; Biomolecules -- Structure; Crystallography; Cytology; Molecular biology; Molecular structure; X-ray crystallography; Periodicals; 548
• DOI: 10.1107/S2059798322011871
• Languages: English
• ISSNs: 2059-7983

Abstract

Abstract : Atomistic simulations enhance protein crystallography, yielding mechanistic insights into a protein kinase involved in the regulation of fundamental biological processes that include metabolism, development, memory and immune response. Abstract : It is investigated whether molecular‐dynamics (MD) simulations can be used to enhance macromolecular crystallography (MX) studies. Historically, protein crystal structures have been described using a single set of atomic coordinates. Because conformational variation is important for protein function, researchers now often build models that contain multiple structures. Methods for building such models can fail, however, in regions where the crystallographic density is difficult to interpret, for example at the protein–solvent interface. To address this limitation, a set of MD–MX methods that combine MD simulations of protein crystals with conventional modeling and refinement tools have been developed. In an application to a cyclic adenosine monophosphate‐dependent protein kinase at room temperature, the procedure improved the interpretation of ambiguous density, yielding an alternative water model and a revised protein model including multiple conformations. The revised model provides mechanistic insights into the catalytic and regulatory interactions of the enzyme. The same methods may be used in other MX studies to seek mechanistic insights.