What is ISOLDE?
ISOLDE is an immersive environment designed to ease the task of building high quality macromolecular models into low to medium resolution experimental maps, where the experimental information alone is insufficient to place individual atoms precisely. Historically this has been exceedingly challenging, for a number of reasons:
- our understanding of how real atoms and molecules behave was limited;
- we didn't have the computational resources to realistically model them at useful speeds anyway; and
- computer graphics were not up to the task of providing intelligible and information-rich interactive visualisations.
Today, none of the above remains true.
Molecular dynamics forcefields such as AMBER and CHARMM provide high-fidelity descriptions of the forces governing most macromolecules and a growing population of small molecule ligands. Molecular dynamics engines such as OpenMM leverage the massively-parallel computing capabilities of modern graphics processing units (GPUs) to solve Newton’s laws of motion for these forces hundreds of times per second on systems of a few thousand atoms. Meanwhile, ChimeraX provides a fast, flexible API allowing the clear, high-speed and rich rendering of the ongoing simulation necessary for it to make sense to human eyes.
Combining the above allows the model-building task to be re-imagined as a truly interactive experience in which, rather than carefully adjusting individual atoms and dihedral angles, the user instead helps to guide a “living”, explicitly physical model into the experimental map. In this way, many of the unlikely or impossible atomic arrangements that plague traditional model-building methods are prevented from ever occurring in the first place, and many other errors simply fix themselves.
What can it do?
- Show you how you're doing, not just how you did
Real-time validation is a major focus in ISOLDE. Common validation tasks have been streamlined, allowing the results of every change to be marked directly on the model in real time.
- Reduce the time spent on manual model building at low resolution
Applying physical forces to the model comes with many advantages - not the least of which is that a great many simple errors simply fix themselves, leaving you to focus on the harder ones. Further, the combination of this physicality with real-time visualisation makes fixing most errors fast and easy.
- Work natively with cryo-EM maps and/or crystallographic data
Any volumetric dataset that ChimeraX opens can be used by ISOLDE. Additionally, ISOLDE will generate maps directly from crystallographic F/sigF data in MTZ format (and automatically re-calculate them when the model changes) and/or generate "static" maps from pre-calculated F/phi data. Any combination of these maps may be used simultaneously with the one model.
What can it not do (yet)?
ISOLDE is a package under active development. The features on the list below are planned for future releases.
- Build in new residues
- Handle alternate conformers
- Refine B-factors
- Handle unusual residues and ligands
Currently, ISOLDE handles only residues that are in the standard AMBER protein and nucleic acid forcefields, plus water and most metal ions. Other species are not yet supported (but progress is being made). If you are a specialist in the field of ligand parameterisation and interested in collaborating, please do get in touch.