NOMAD-Ref: visualization, deformation and refinement of macromolecular structures based on all-atom normal mode analysis

Abstract

Normal mode analysis (NMA) is an efficient way to study collective motions in biomolecules that bypasses the computational costs and many limitations associated with full dynamics simulations. The NOMAD-Ref web server presented here provides tools for online calculation of the normal modes of large molecules (up to 100,000 atoms) maintaining a full all-atom representation of their structures, as well as access to a number of programs that utilize these collective motions for deformation and refinement of biomolecular structures. Applications include the generation of sets of decoys with correct stereochemistry but arbitrary large amplitude movements, the quantification of the overlap between alternative conformations of a molecule, refinement of structures against experimental data, such as X-ray diffraction structure factors or Cryo-EM maps and optimization of docked complexes by modeling receptor/ligand flexibility through normal mode motions. The server can be accessed at the URL http://lorentz.immstr.pasteur.fr/nomad-ref.php.

Figure 1

Flow chart of the NOMAD-Ref server.

Figure 2

Refinement of the first 10 lowest frequency amplitudes of citrate synthase open form (5CSC) based on simulated Cryo-EM data at 15 Å resolution for the closed form (6SCS). In green, the control experiment is made by conducting the refinement against a cRMS score between the two forms.

Figure 3

Receptor-ligand docking refinement for glutamine-binding protein (1GGG/1WDN). (A) Intermolecular soft-core nonbonded energy landscape as a function of the two first non-rigid-body normal mode amplitudes. (B) Ligand docked with initial (open) receptor conformation (red) superimposed on closed state (blue)—5.33 Å cRMS. (C) Receptor structure refined using the five lowest normal modes compared to the target closed state—2.16 Å cRMS. The five degrees of freedom reduce the cRMS by a factor two.