Adorym: A multi-platform generic x-ray image reconstruction framework based on automatic differentiation

We describe and demonstrate an optimization-based x-ray image reconstruction framework called Adorym. Our framework provides a generic forward model, allowing one code framework to be used for a wide range of imaging methods ranging from near-field holography to and fly-scan ptychographic tomography. By using automatic differentiation for optimization, Adorym has the flexibility to refine experimental parameters including probe positions, multiple hologram alignment, and object tilts. It is written with strong support for parallel processing, allowing large datasets to be processed on high-performance computing systems. We demonstrate its use on several experimental datasets to show improved image quality through parameter refinement

STRUCTURE DETERMINATION OF HETEROGENEOUS BIOLOGICAL SPECIMENS IN CROWDED ENVIRONMENTS

The central dogma of molecular biology describes a strictly linear flow of genetic information stored in DNA transferred through RNA and translated into protein products. In the “post-genomic era” however, it is evident that abundant information flows from protein to protein and even protein back to DNA. The field of Structural Biology seeks to understand how the spatial and temporal organization of that information is stored and transmitted via the three-dimensional structure and dynamics of biological macromolecules. X-ray crystallography, nuclear magnetic resonance, and single particle cryo-electron microscopy (cryo-EM) are the primary techniques available to the structural biologist to deduce structure and dynamics at or near atomic resolutions. These tools are generally limited to the study of stable molecules that can be purified biochemically. Other approaches, like super-resolution light microscopy and cryo-electron tomography (cryo-ET), are amenable to the study of more labile macromolecular complexes or those found in situ; however, they are limited to resolutions of tens of nanometers. Improving the resolving capability of cryo-ET with sub-tomogram averaging to routinely reach beyond 10 Å is the primary goal of this work. My unique contribution to the field of structural biology is a suite of software tools called emClarity (enhanced macromolecular classification and alignment for high-resolution in situ tomography) which allows scientists with minimal computational background to probe the structural states of conformationally variable molecules present in complex and crowded environments