Hemochromatosis Normal modes

Labjournal_NMA-Hemochromatosis

<figure id="timescale">

Timescale of protein motions <ref name="timescale_motions"> Normal Mode Analysis of Biomolecular Structures: Functional Mechanisms of Membrane Proteins Ivet Bahar, Timothy R. Lezon, Ahmet Bakan, and Indira H. Shrivastava Chemical Reviews 2010 110 (3), 1463-1497</ref>

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Introduction

WebNMA and elNemo are two different web servers for normal mode analysis. Both provide different information:

• WebNMA
  • normal modes + animations
  • average residue fluctuations
  • correlated residue movement map

• elNemo
  • normal modes + animations
  • average residue fluctuations
  • pairwise correlated residue movement as a list

The modes are only calculated from the C-alpha atoms of the proteins residues. In principal, 3N-6 normal modes could be computed, where N is the number of atoms in the molecule. The reasoning behind this number is, that each atom in a molecule has three coordinates and the molecule thus has 3N degrees of freedom. However, three degrees of freedom have to be omitted to account for translation and another three have to be omitted to account for rotational symmetry. For the HFE protein with 272 residues, 810 normal modes can be calculated, but only the low frequency normal modes are of interest, because they resemble slow motions.

elNemo

Mode 7	Mode 8	Mode 11	Mode 12	Mode 13
This mode shows a hinge motion about the connection between the two domains. The immunoglobulin domain and the MHC-like domain move towards each other.	This mode also shows a hinge motion about the domain connection, but in this case, the Ig domain twists away from the upward moving MHC-like domain.	A hinge motion of the Ig domain and a breathing motion of the MHC-like domain are shown in this figure.	Mode 12 and 13 both show a slight hinge motion of the Ig domain and a strong breathing motion of the MHC-like domain. This observation can be expected, because the MHC domain is part of the binding interface of B and T cells. This interface needs to be flexible, because those cells bind to different cells types.

WebNM@

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Mode	Deformation Energy
7	325.91
8	817.13
9	849.13
10	1452.95
11	1876.97
12	2972.27

<figtable id="webnma_modes7to12">

Table 3: Visualization of the normal modes 7 to 12 for 1A6Z chain A. The original protein structure is shown in green and the movement of the C alpha atoms is shown as a red ribbon.

	Mode 7	Mode 8	Mode 9	Mode 10	Mode 11	Mode 12

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Domain definition

<figure id="fig:corr_motions">

Correlated residue motions for the HFE protein

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Figure <xr id="fig:corr_motions" /> shows two distinct zones with correlated movement. The first zone starts at the beginning of the sequence and ends at residue 175. The second zone starts at residue 176 and extends until the end of the sequence. Based on this observation, two domains can be assigned two the two zones. SCOP, CATH and Pfam all assign the same two domains to the HFE protein <xr id="fig:1a6z_domains" />, the MHC I domain(green) and the Ig domain (blue). This is in complete accordance with the domain assignment based on the correlated motion matrix.

<figtable id="fig:1a6z_domains">

Side

Front

Top

</figtable> CATH MHC domain CATH Ig domain

SCOP MHC domain SCOP Ig domain

Pfam domains

Flexibility

<figure id="fig:fluctuations">

The square of the fluctuation of each C-alpha atom (for all non-trivial modes), normalized so that the sum over all residues is equal to 100. The fluctuations are the sum of the atomic displacements in each mode weighted by the inverse of their corresponding eigenvalues.

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<figtable id="fig:3d_fluc">

Table X: The flexibility of the C-alpha atoms is shown color coded, where red indicates no flexibility, white indicates medium flexibility and blue indicates high flexibility.

	Side	Front

</figtable>

Figure <xr id="fig:fluctuations" /> shows some highly flexible regions connected by rigid stretches. Another way to look at the C-alpha fluctuation data is shown in figure <xr id="fig:3d_fluc" />. The more flexible regions are almost exclusively located at the ends of the protein, that are farthest away from the hinge, that is the stretch, that connects the two domains.

Comparison of Molecular Dynamics and Normal Mode Analysis

In comparison to Molecular Dynamics, normal mode analysis can grasp the slow and globular motions of a protein. Although it can only grasp the harmonic part of these motions, it gives a good insight into them at comparably low computational cost. MD takes the influence of the side chains into account by modeling them explicitly, whereas NMA only takes them into account implicitly through the position of the C-alphas. Thus, MD can model the effect of side chain movements and SNPs on the proteins dynamics, whereas NMA cannot do this.

References

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