Atomistic modelling of scattering data in the Collaborative Computational Project for Small Angle Scattering (CCP6sas): new insight into antibody conformations

The CCP-SAS project is currently developing open source software for the atomistic and coarse-grained molecular modelling of X-ray and neutron small-angle scattering data (Perkins et al., 2016). Its computational framework will be described, alongside applications in immunology. CCP-SAS software provides a unique opportunity to model small angle scattering data for antibodies at the atomistic level, and to include other structural constraints ranging from molecular and atomistic energetics to crystallography, electron microscopy and NMR.  This extends the capabilities of solution scattering and provide deeper insights into the biophysics and biochemistry of the proteins being studied. Realizing this potential however, requires integrating the experimental data with a new generation of modelling software. To achieve this, the CCP-SAS collaboration (http://www.ccpsas.org/) is developing high-throughput, and user-friendly software for the atomistic and coarse-grained molecular modelling of scattering data. Robust state-of-the-art molecular simulation engines and molecular dynamics and Monte Carlo force fields provide constraints to the solution structure inferred from the small-angle scattering data. In CCP-SAS, GenApp provides the deployment infrastructure for running applications on both standard and high-performance computing hardware, and SASSIE provides a workflow framework into which modules can be plugged to prepare structures, carry out simulations, calculate theoretical scattering data, and compare results to experimental data. Thus GenApp produces the accessible web-based front end termed SASSIE-Web, and GenApp and SASSIE also make community SAS codes available. Applications of this CCP-SAS methodology will be illustrated by case studies of human antibodies important in biotechnology and disease. These include the four IgG subclasses, as well as the IgA and IgE classes, for all of which the first atomistic solution structures have been determined by a combination of X-ray and neutron scattering.

Reference: Perkins SJ, Wright DW, Zhang H, Brookes EH, Chen J, Irving TC, Krueger S, Barlow DJ, Edler KJ, Scott DJ, Terrill NJ, King SM, Butler PD & Curtis JE (2016) Atomistic modelling of scattering data in the Collaborative Computational Project for Small Angle Scattering (CCP-SAS). J. Appl. Crystal. 49, 1861-1875.