Development of likelihood-based methods in structural biology (360G-Wellcome-209407_Z_17_Z)

<p>I propose to build on our development of new likelihood-based methods for structural biology, transposing approaches that have had great impact in macromolecular crystallography to the new area of cryo-EM.&nbsp; 1) In crystallography we will enable the solution of difficult structures (poor data or poor starting models) that still evade current methods.&nbsp; New statistical innovations will automate the clustering of alternative molecular replacement models into sensible ensembles representing different conformations. &nbsp;2) We will exploit a promising new approach to the determination of substructures for SAD phasing, based on our SAD likelihood function.&nbsp; 3) In cryo-EM we will investigate the propagation of errors in reconstructions, building on this understanding to devise improved likelihood-based methods to dock atomic models into cryo-EM maps, particularly those challenging cases determined at low resolution such as sub-tomogram averages.&nbsp; The implications of multi-variate cryo-EM likelihood targets will be explored, with potential applications in the angular deconvolution of cryo-EM maps.&nbsp; 4) Finally, we will develop a new approach to modelling macromolecular structures at low resolution, using interactive molecular dynamics flexible fitting to combine high-quality potential functions with likelihood targets.</p>