3D Analysis (Week6)

3D Analysis of FBN1:

The PBD ID for this structure : 1LMJ.

Using NCBI "structure" and the protein FBN1, 9 results were obtained. I chose to use PBD ID: 1LMJ because it is a human protein structure, recently updated (in 2013), and a structural protein that contained the region of substitution (codon 1137: Arginine (CGC) is replaced with Proline (CCC).)

Using Cn3D, the FBN1 protein is depicted below:

Utilizing Cn3D, a space filling view of the protein is depicted below with position 1137 highlighted in yellow. The site is externally placed on the protein.

Space filling view of Position 1137

Upon zooming in and utilizing the "worms" view in Cn3D, the following image was obtained. Position 1137 is highlighted in yellow (and circled in red). It appears that position 1137 is located on a beta sheet within the molecule.

Worms view of position 1137

Upon review of the secondary structures from last week, the Garnier Robson and Chou Fasman methods predicted position 1137 to be located on a turn region, not on an alpha helix or beta sheet. Utilizing the file obtained fron NCBI "structure" and reviewing it in Protean 3D (as illustrated below), the secondary structure reveals position 1137 to be on a beta sheet. Hence, both algorithms from last week incorrectly predicted the position of 1137.

With regards to prediction of hydropathy, Kyte Doolittle algorithm predicted a hydrophilic region which was correctly identified. This is portrayed on the space filling view as noted above.

Overall view of position 1137 in Protean 3D

Position 1137 located on a beta sheet

Protein Structure Prediction, human variation (Week 5)

.0001 MARFAN SYNDROME, SEVERE CLASSIC

FBN1, ARG1137PRO [dbSNP:rs137854456] ClinVar

According to OMIM, a G to C transversion at nucleotide 3410 converted codon 1137 from CGC (arginine) to CCC (Proline) is associated with this gene. This mutation was previously known as ARG239PRO. This is a nonconservative change where a basic amnio acid is replaced with a nonpolar alpha-amino acid proline. There appeared to be no clinical impact of this mutation as the two original patients this was identified in did not show any abnormalities. 

Protein Analysis:

The substitution of Arginine with Proline on Codon 1137 did not have any significant impact on the secondary structure, hydropathy, or transmembrane region of the protein. The alpha and  beta regions of the secondary structure are hydrophilic and the same was noted on the variant mutation. Upon magnification of the Kyte Doolittle regions, all areas remained hydrophobic in both sequences. There was no change on the transmembrane regions of the protein. 

Original Sequence: Overall view of secondary structure

Original sequence: Magnified view of secondary structure

Variant Sequence: Overall view of secondary structure

Variant sequence: Magnified view of secondary structure

Orignial sequence: Overall view of Kyte Doolittle Regions

Originial sequence: Magnified view of Kyte Doolittle Region

Variant sequence: Overall view of Kyte Doolittle Region

Variant Sequence: Magnified view of Kyte Doolittle Region

Originial sequence: Overall view of transmembrane regions

Originial sequence: Magnified view of transmembrane regions

Variant sequence: Overall view of transmembrane regions

Variant sequence: Magnified view of transmembrane regions

Originial Sequence Helical Wheel

Variant Sequence Helical Wheel