To fulfill their biochemical role, many macromolecules catalyze coordinated chemical reactions by undergoing complex conformational motions. If the dynamics of the conformational and chemical changes are modeled accurately, a fuller understanding of the underlying basis of their function can be achieved. Recently, we described a simple user-level strategy called "restrained geometries and topology switching" (RGATS) to use standard molecular mechanics (MM) software to model biochemical reactions. RGATS enables the full assortment of computational methods implemented in any MM software to be used to seamlessly model the full range of any conformational and chemical changes involved in macromolecular function. While the chemical changes are modeled only at a structural level, many questions related to the links between dynamics, environmental changes, and function can still be addressed at very low computational expense. In addition, prior deposited structural data can be used to instantaneously predict plausible structural variations, which can help generate a more comprehensive structural ensemble. The application of this strategy to model the full range of conformational and chemical changes required for macromolecular function will be demonstrated using a few representative examples, including nucleotide addition by DNA polymerases and protein splicing by inteins.

Leveraging structural and chemical knowledge to clarify the role of dynamics in macromolecular function

256th National Meeting (2018)

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