Abstract
The capabilities of current computer simulations provide a unique opportunity to model small-angle scattering (SAS) data 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 provides deeper insights into the physics and chemistry of the systems 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 open-source, 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, which incorporates the known physical chemistry of the system. The implementation of this software suite involves a tiered approach in which 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 with experimental data. GenApp produces the accessible web-based front end termed SASSIE-web, and GenApp and SASSIE also make community SAS codes available. Applications are illustrated by case studies: (i) inter-domain flexibility in two- to six-domain proteins as exemplified by HIV-1 Gag, MASP and ubiquitin; (ii) the hinge conformation in human IgG2 and IgA1 antibodies; (iii) the complex formed between a hexameric protein Hfq and mRNA; and (iv) synthetic 'bottlebrush' polymers.
Highlights
Small-angle X-ray scattering (SAXS) and neutron scattering (SANS) are diffraction techniques for investigating a broad range of science
To illustrate some representative atomistic modelling workflows, we summarize applications of SASSIE-web to a broad range of systems in biology and soft matter (Fig. 1) (Datta et al, 2007; Nan et al, 2017, unpublished work; Castaneda, Chaturvedi et al, 2016; Castaneda, Dixon et al, 2016; Clark et al, 2013; Hui et al, 2015; Peng et al, 2014; Zhang et al, 2014)
If a critical nonopen-source component is needed, it can be incorporated, but an alternative open-source solution is identified to replace this as quickly as possible. This policy accommodates the drive for open-source software for proper validation and transparency increasingly requested by funding bodies and helps engage community support
Summary
Small-angle X-ray scattering (SAXS) and neutron scattering (SANS) are diffraction techniques for investigating a broad range of science. The other new element in SASSIE was the incorporation of Monte Carlo (MC) simulation methods to create ensembles of biomolecular structures by sampling user-selected backbone dihedral angles to model experimental X-ray and neutron data. Without this advance, the generation of atomistic structures using modern forcefield-based simulations could take months or even be inaccessible. In order to reveal how atomic level molecular structures in biological or soft matter systems account for experimental scattering data, the Collaborative Computational Project for Small Angle Scattering (CCP-SAS), jointly funded by the EPSRC research council in the UK and the National Science Foundation in the USA, was created in 2012 to address these issues of access and long-term sustainability. To illustrate some representative atomistic modelling workflows, we summarize applications of SASSIE-web to a broad range of systems in biology and soft matter (Fig. 1) (Datta et al, 2007; Nan et al, 2017, unpublished work; Castaneda, Chaturvedi et al, 2016; Castaneda, Dixon et al, 2016; Clark et al, 2013; Hui et al, 2015; Peng et al, 2014; Zhang et al, 2014)
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