Fabry:Normal mode analysis

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Fabry Disease » Normal_mode_analysis

Introduction

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Maybe one of the first questions that can be asked in this task is, why we use low-frequency normal modes. This is explained in the paper of Marc Delarue and Philippe Dumas<ref>Marc Delarue and Philippe Dumas On the use of low-frequency normal modes to enforce collective movements in refining macromolecular structural models, Proc. Natl. Acad. Sci. (USA), 101, 6957-6962 (2004)</ref>, where they claim, that "many of the structural transitions (...) can be explained by just a few of the lowest-frequency normal modes". The normal modes can be used to generate the general motion of a system by superposition them. Thus we could in principle infer from our analysis in this task how the alpha-galactosidase A, which we examine hydrolyses the terminal alpha-galactosyl moiety of its substrate<ref>Normal mode http://en.wikipedia.org/wiki/Normal_mode, July 5th, 2012</ref>.


WEBnm@

WEBnm@ <ref>Hollup SM, Sælensminde G, Reuter N. WEBnm@: a web application for normal mode analysis of proteins BMC Bioinformatics. 2005 Mar 11;6(1):52 </ref> claim to administer simple and automated computation of low-frequency normal modes for proteins as well as their analysis in order to clarify if it is beneficial to perform a complete study on the protein in question.
The server calculates Normal Modes with the help of the MMTK package <ref>Hinsen K, The Molecular Modelling Toolkit: a new approach to molecular simulations, J Comput Chem, 21:79-85, 2000</ref>, which is an Open Source program library for molecular simulation applications. A C-alpha force field <ref>Hinsen K, Petrescu AJ, Dellerue S, Bellissent-Funel MC, Kneller GR, Harmonicity in slow protein dynamics, Chemical Physics, 261:25-37, 2000</ref> is used and only these C-alpha atoms are used, but with a weight assigned that corresponds to the masses of the whole residue they represent.
The server provides a bunch of analysis tools and all results can be downloaded without any problems. The tools are:

  • deformation energies of each mode
  • eigenvalues
  • calculation of normalized squared atomic displacements
  • calculation of normalized squared fluctuations
  • interactive visualization of the modes using vector field representation or vibrations
  • correlation matrix

<figtable id="tab:webnma_3hg2"> In this table are the 6 modes shown, that were calculated by WEBnm@. Depicted is the structure 3HG2, which represents the Human α-galactosidase catalytic mechanism with empty active site in cyan and the substrate binding site at position 203 to 207 highlighted in red.

WEBnm@ mode 7 of 3HG2
WEBnm@ mode 8 of 3HG2
WEBnm@ mode 9 of 3HG2
WEBnm@ mode 10 of 3HG2
WEBnm@ mode 11 of 3HG2
WEBnm@ mode 12 of 3HG2

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<figtable id="tab:webnma_3hg3"> In this table are the 6 modes shown, that were calculated by WEBnm@. Depicted is the structure 3HG3, which represents the Human α-galactosidase catalytic mechanism with bound substrate (green, α-D-Galactose with bound α-D-Glucose) in cyan and the substrate binding site at position 203 to 207 highlighted in red.

WEBnm@ mode 7 of 3HG3
WEBnm@ mode 8 of 3HG3
WEBnm@ mode 9 of 3HG3
WEBnm@ mode 10 of 3HG3
WEBnm@ mode 11 of 3HG3
WEBnm@ mode 12 of 3HG3

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Average Energies

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3HG2 3HG3
406.07 318.52
580.11 508.88
1062.04 1078.20
1703.56 1621.95
1808.92 1827.08
2227.10 2019.97
2541.59 2481.89
3109.43 2695.35
3345.86 3321.12
3842.69 3588.18
4868.07 3782.94
5178.29 4404.61
6119.79 5349.94
5940.89 6027.59

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Atomic Displacement Analysis

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Plots the displacement of each Calpha atom, i.e. highlights which parts of the protein are the most displaced for each mode.


ElNemo


References

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