Structural ensemble reconstruction for Intrinsically disordered proteins via a physics-based coarse-grained model guided by NMR parameters
Kierownik projektu: Adam Liwo
- Yi He
- Shenghan Song
- Amy Stevens
- Tongtong Li
Data otwarcia: 2021-08-13
Because chemical shifts (CS) from NMR experiments can be measured under a wide range of conditions with great accuracy, CS have become the most accessible parameter for structural characterization of flexible proteins. Furthermore, the incorporation of experimental data in computational modeling can improve the accuracy of computational predictions and ultimately fill the gap of missing information. Recently, we have developed a single-residue based chemical shift-protein structure database and a complimentary program called Glutton. Glutton is about 1000 times faster than an all-atom sampling of the conformation space. Moreover, Glutton can identify multiple structural preferences corresponding to only one set of chemical shifts for residues which fluctuated between multiple states rather than only one structure. With the torsional angle restrictions obtained from Glutton, we will modify the UNRES force field by including γ angle distributions to achieve a more complete search of the conformational space using multiplexed replica exchange molecular dynamics (MREMD). MREMD has been proven to better sample the conformational space, as demonstrated in previous works. Furthermore, we will include an additional energy term to better reflect the sampling of unstructured proteins. A fine-grained cluster analysis based on free energies will be used to obtain a structural ensemble of 10,000 structures. The developed chemical shift-UNRES program will be validated using ASC protein experimental data provided by Dr. Eva De Alba at the University of California Merced. The chemical shift data will be used to guide the simulations, and the Residual Dipolar Coupling (RDC) and Nuclear Overhauser effect (NOE) data will be used to validate simulation results independently.
Our aim is to optimize the UNRES force field so that it can effectively and accurately sample the conformational space of disordered proteins. In addition, we will develop a strategy to guide UNRES simulations with dihedral angle distributions extracted from NMR chemical shift data via Glutton. With the above goals, we would like to request access to Tryton supercomputer and related storage system. This access will allow us to benchmark and optimize the UNRES force field and, ultimately, test the final strategy of NMR chemical shift-guided UNRES simulations.
The TASK supercomputer has the developer/latest version of UNRES, which is critical for the completion of the project. The computational power provided for the Tryton supercomputer is needed for optimization and extensive evaluation of the optimized UNRES force fields with real-world applications.