Combining molecular dynamics simulations with crystallographic refinement

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The principal goals of this project are the development of algorithms that allow one to make better con- nections between molecular simulations using force fields and the interpretation of crystallographic data on biomolecules. This will involve the following components: Improved models for X-ray scattering from bulk solvent. Most crystallographic refinements protocols try to place a few “ordered” solvent (water) molecules into the observed density, and treat the remaining solvent space as arising from a flat density. Neither part of this model is physcially correct: very few solvent molecules are really ordered, and the bulk is far from flat. This project will explore alternate methods for describing the scattering contribution from solvent, based on integral equation models and explicit molecular dynamics simulations. This is expected to lead to a more correct description of the solvent environment, which it turn should lead to more accurate electron densities and interpretations for the biomolecules themselves Improved models for biomolecular motion and conformational heterogeneity. The standard model for crys- tallographic refinement treats motion and heterogenety via optimization of atomic displacement parame- ters (ADPs) and some combination of rigid-body (TLS) motions for certain subsets of the biomolecule, along with the specification of “alternate conformations” where this can be determined from an examina- tion of the density. The proper description of correlated motions in crystals is likely to be key in obtaining better models for X-ray scattering, but relatively little is known about what motional models are the most physically realistic. Molecular dynamics simulations of super-cells (many unit cells) of biomolecular crys- tals will be used to examine these issues, with particular attention to the question of how well refined TLS parameters are likely to correspond to physical motions. Using modern force fields to guide X-ray refinement. My group has collaborated for about two years with the Phenix development team to create a software environment that can use modern force fields (as imple- mented, for now, in the Amber simulation package) to complement or replace geometric restraints of the Engh-Huber variety with the forces arising from a periodic molecular mechanics model. The initial version of this will be released in the Spring of 2016, and goes a long way towards automating the process from a user's perspective: running a preparation script and setting useAmber=true is often enough to turn on the new procedure. But much remains to be done: allowing for alternate conformations, ensemble-based refinement, and incorporation of implicit solvent models in a periodic environment will be top priorities, as will be more extended testing and incorporation of user feedback.