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 .

Computational analysis of deleterious missense mutations in aspartoacylase that cause Canavan’s disease

“…We also confirmed the mutation position and the mutation residue in PDB ID 2I3C. The mutation was performed in silico using the SWISSPDB viewer, and NOMAD-Ref server performed the energy minimization for 3D structures [30]. This server uses Gromacs as the default force field for energy minimization, based on the methods of steepest descent, conjugate gradient, and limited-memory Broyden-Fletcher-GoldfarbShanno (L-BFGS) methods [31].…”

“…Mutations at a specified position were performed in silico by SWISSPDB viewer independently to obtain a modeled structure. NOMAD-Ref server [30] and ifold server [32] performed the energy minimizations and stimulated annealing respectively, for both native structure and the 22 mutant modeled structures. To determine the deviation between the native structure and the mutants, we superimposed the native structures with all 22 mutant modeled structures and calculated the RMSD.…”

“…point mutation using the SWISSPDB viewer for the 22 variants. Energy minimization was performed by NOMAD-Ref [30], followed by stimulated annealing by ifold [32] server to obtain optimized structures for both the native and mutant proteins.…”

Identification of aspartic acid-203 in human thymidine phosphorylase as an important residue for both catalysis and non-competitive inhibition by the small molecule “crystallization chaperone” 5′-O-tritylinosine (KIN59)

“…To probe the flexibility of this enzyme, an elastic network model was used in which all non-hydrogen protein atoms (within a cutoff of 10 Å ) were modeled as point masses and Ca atoms were connected by springs representing the interatomic force fields. Monomer A was analyzed as a large set of coupled harmonic oscillators using the normal mode analysis, deformation and refinement (NOMAD-Ref) server [29] and default parameters. The conformational changes were deduced by calculating the 10 lowest-frequency normal modes, which are those with the highest amplitudes and those most often related to large-scale structural rearrangements in proteins.…”

Conformational dynamics of supramolecular protein assemblies

“…While several data banks and servers [22][23][24][25][26][27] exist to disseminate publically the conformational dynamics of protein structures deposited in the PDB, similar data banks do not exist at present for the EMDB. Such a data bank would support both further computational analyses to gain insight into the biological function of high molecular weight protein assemblies lacking atomic structure, as well as potentially serve as a basis set for classification in singleparticle reconstruction [28].…”