Showing papers by "Paul C. Whitford published in 2018"

Disorder guides domain rearrangement in elongation factor Tu.

Abstract: Elongation factor Tu (EF-Tu) is a three-domain protein that is responsible for delivering aminoacyl-tRNA (aa-tRNA) molecules to the ribosome. During the delivery process, EF-Tu undergoes a large-scale (~50A) conformational transition that results in rearrangement of domain I, relative to the II/III superdomain. Despite the central role of EF-Tu during protein synthesis, little is known about the structural and energetic properties of this reordering process. To study the physical-chemical properties of domain motion, we constructed a multi-basin structure-based (i.e., Gō-like) model, with which we have simulated hundreds of spontaneous conformational rearrangements. By analyzing the statistical properties of these events, we show that EF-Tu is likely to adopt a disordered intermediate ensemble during this transition. We further show that this disordered intermediate will favor a specific sequence of conformational substeps when bound to the ribosome, and the disordered ensemble can influence the kinetics of the incoming aa-tRNA molecule. Overall, this study highlights the dynamic nature of EF-Tu by revealing a relationship between conformational disorder and biological function.

Using SMOG 2 to simulate complex biomolecular assemblies

Abstract: Over the last 20 years, the application of structure-based (Go-like) models has ranged from protein folding with coarse-grained models to all-atom representations of large-scale molecular assemblies. While there are many variants that may be employed, the common feature of these models is that some (or all) of the stabilizing energetic interactions are defined based on knowledge of a particular experimentally-obtained conformation. With the generality of this approach, there was a need for a versatile computational platform for designing and implementing this class of models. To this end, the SMOG 2 software package provides an easy-to-use interface, where the user has full control of the model parameters. This software allows the user to edit XML-formatted files in order to provide definitions of new structure-based models. SMOG 2 reads these ''template'' files and maps the interactions onto specific structures, which are provided in PDB format. The force field files produced by SMOG 2 may then be used to perform simulations with a variety of popular molecular dynamics suites. In this chapter, we describe some of the key features of the SMOG 2 package, while providing examples and strategies for applying these techniques to complex (often large-scale) molecular assemblies, such as the ribosome.