Ramy Farid is Schrödinger’s Senior Vice President of Scientific Development and Program Management. In addition to overseeing all scientific software development at Schrödinger, Dr. Farid has been heavily involved in the development of PrimeX, a forthcoming application for protein crystallographers.
A key aspect to the successful development of scientific software is to identify not only research problems that can be overcome with the aid of software applications, but to also recognize opportunities in which well-established technology can be adapted to solve those problems. After carefully considering how to best create an application for X-ray structure refinement, we are now in the process of developing an application for crystallographers that uses technology derived from both our docking program (Glide) and our protein structure prediction software (Prime).
Producing an accurate model is implicit in the refinement process for an X-ray structure, and placing small molecules into electron density is one of the laborious chores that could be expedited using computational methodologies. While Prime accurately predicts protein structures through the use of an advanced all-atom force field and implicit solvent model, Glide accurately predicts the conformation and pose for a ligand bound to a receptor structure. The realization that these technologies have applications in X-ray structure determination has put us on the path to producing an X-ray refinement package. We call this software PrimeX because of its technological underpinnings.
Our goal with the first release of PrimeX is to provide protein crystallographers with all the tools they need to completely refine structures, starting from an initial molecular replacement model and ending with publication-ready coordinates. PrimeX incorporates a full range of real-space and reciprocal-space refinement methods. Crystallographers will be able to rapidly and accurately predict the conformation of loops and side chains with Prime-based tools that are guided by the observed electron density, and they will be able to place ligands and other small molecules using real-space density fitting with assistance from Glide.
Reciprocal-space refinement using truncated Newton minimization with least-squares or maximum-likelihood targets will also be supported in PrimeX. Rigid body and individual coordinate refinement will be available, as well as individual B-factor and grouped occupancy refinement. In addition, molecular dynamics simulated annealing will be provided, drawing on technology already implemented in Schrödinger’s Impact module. This simulation technology was developed in collaboration with Ron Levy’s group at Rutgers University.
PrimeX will be fully integrated into the Maestro graphical user interface. Maestro itself will be augmented to support PrimeX functions, including additional methods for manual model manipulation. Electron density maps will be easily visualized in the forthcoming release, and tools will be added for X-ray structure validation using both molecular geometry and electron density fit.
The alpha version of PrimeX is currently undergoing internal testing, with the beta version scheduled for release later this year. We look forward to incorporating changes based on feedback that we obtain during the beta period, and anticipate a successful launch of PrimeX early next year.
As with all our products, development of PrimeX will not end with the initial software release. Our long-term roadmap for PrimeX involves ongoing development efforts to implement new features. We plan on exploring alternative statistical treatments of phasing that will advance our present maximum likelihood model. Research will also continue into the combination of validation and fitting tools, leading to more extensive automated units, which in turn will reduce the amount of intervention required by the crystallographer during the refinement process. Prime’s advanced capabilities make such automation a very promising direction for the future of PrimeX development.