Data Analysis for Structural Biology

Protein structures can be studied using experiments, including nuclear magnetic resonance (NMR), cryo-Electronic microscopy (CryoEM), and X-ray crystallography. One focus of our research is to investigate the properties and basic information of these high resolution structures in some systematic ways, or ‘structural bio-informatics’.

High resolutions models are preferred if they can be determined, yet some experimental methods provides limited information about the structures, from which only rough models at low resolutions can be obtained. A widely used method is solution scattering, which has advantages, such as easy sample preparation, high throughput, capability of probing dynamics, and near in vivo environments. We develop methods to extract information from such scattering data (Small Angle X-ray Scattering, or Wide Angle X-ray Scattering). Our goal is to build models from scattering data, or refinement known structures with respect to scattering information.

XFEL

X-rays have been applied in structure determination for a century (celebrating the international year of crystallography). A major breakthrough of X-ray science is the commission of X-ray Free Electron Lasers, or XFELs (FLASH at Hamberg; LCLS at SLAC; SACLA at Spring8), The Linac Coherent Light Source is the first commissioned Hard X-ray facility, providing ultra bright, fully coherent X-ray pulses at up to 120Hz. The pulse duration is at femtosecond time scale, yet compressing ~10^12 X-ray photons per pulse to very focused area. The peak brilliance of the LCLS is 10 orders higher than the third generation synchrotron facilities. Every pulse vaporizes the samples rapidly, but the illumination stops within femtoseconds (pulse duration). Such intense femtosecond pulses could outrun radiation damages, enables a revolutionary experimental approach: diffract-before-destroy. New experiments are designed to exploit this unprecedented technology. High resolution structure determination from tiny crystals smaller than 1 micron emerges and develops very rapidly; exports have been made to imaging single particles, even single molecules, using such bright X-ray lasers.

Serial Femtosecond Nano-crystallography ( SFX ) is one of the killer applications of the Free Electron Laser X-rays. Every XFEL pulse that intercept a crystal can generate diffraction patterns, and after indexing and merging a large number (often > 10s of thousands) of such diffraction patterns, a 3D diffraction volume can be obtained. From there, phasing algorithms developed for synchrotron crystallography can be applied. Our research focus is on data analysis procedures from raw data to integrated 3D diffraction volume. More specifically, we work on (1) background correction; (2) resolving indexing ambiguity due to crystal twinning, i.e., detwinning by utilizing intensity information; (3) optimizing data merging methods; (4) new phasing algorithms for nano crystallography.

Single Particle Imaging using X-ray Lasers is the ultimate goal of FEL facilities. According to simulations, the femtosecond XFEL pulses should be able to probe structure information from noncrystalline materials, such as single particles, or even single protein molecules. Since the commission of LCLS, huge efforts have been devoted to the development of single particle imaging using X-rays. In order to assemble the 2D scattering patterns resulted from the interaction between X-rays and randomly oriented sample particles, advanced computer algorithms must be developed. There are some progresses from pure mathematical and computational perspectives, but none of such methods have been successfully applied to actual experimental data yet. Some breakthrough has to be made in order to realize 3D model reconstructions using femtosecond X-ray scattering data.

CryoEM

Single molecule fluorescence tracking

Molecular Dynamics Simulations

Group Dynamics in animal behaviours

Richard Feynman

“everything that is living can be understood in terms of the jiggling and wiggling of atoms”.

and now, we want to watch atoms jiggling and wiggling.

X-rays, electrons, fluorescence light, the advances of photon sciences, together with computational modeling, are making this happen.