In silico conformational assay

Molecular dynamics to study protein flexibility

What is it?

Folded proteins change their conformation in varying degrees, ranging from simple pocket breathing to large rearrangements of entire domains, like the spike protein of some viruses. While crystal structures can help enormously understanding your target, they only offer a static picture, a small well of the conformational landscape of your target.

With molecular dynamics, we can further explore this landscape, visiting other relevant wells, such as the active conformation of a GPCR, or the DFG-out conformation of a kinase. In collaboration with UCB, we transitioned the structure of a GPCR from its inactive to its active conformation, using unbiased simulations.

With our adaptive sampling protocol, we can study the conformational landscape of your protein in a cost-effective manner, revealing structural insights which can directly impact your drug discovery campaign.

What is the value of this service?

  • Unique structural insights: Knowing the different conformations that your target can adopt, can give you and edge.
  • Ensemble docking: Build an ensemble of pocket conformations to do ensemble docking.
  • Understanding the transition: Visualize how the spike protein of a virus adopts the host-bound-ready state, or how a GPCR goes from inactive to active
  • Estimate conformational stability: Is a particular mutant more likely to stay in a given conformation than the wild-type?

What will you obtain?

Deliverables include:

  • A PyMol or VMD scene with the most relevant conformations.
  • The full simulations (.xtc and .pdb files).
  • An extensive report summarizing the structural insights obtained.
  • Conference calls with the team to discuss the results.

References

  1. Martinez-Rosell, G., Lovera, S., Sands, Z. A., & De Fabritiis, G. (2020). PlayMolecule CrypticScout: Predicting Protein Cryptic Sites Using Mixed-Solvent Molecular Simulations. Journal of Chemical Information and Modeling, 60(4), 2314–2324. https://doi.org/10.1021/acs.jcim.9b01209

  2. Arcon, J. P., Defelipe, L. A., Modenutti, C. P., López, E. D., Alvarez-Garcia, D., Barril, X., Turjanski, A. G., & Martí, M. A. (2017). Molecular Dynamics in Mixed Solvents Reveals Protein-Ligand Interactions, Improves Docking, and Allows Accurate Binding Free Energy Predictions. Journal of Chemical Information and Modeling, 57(4), 846–863. https://doi.org/10.1021/acs.jcim.6b00678

alejandroIn silico protein conformation analysis