Image reproduced under Creative Commons licence. Source: Wikimedia commons
The Cellular Prion Protein (PrPc) like Dr. Jekyll converts into PrPSc , a fatal conformational form, like Mr. Hyde, and is responsible for a variety of neurodegenrative disorders. Unlike the use of a potion, this molecular Jekyll and Hyde undergoes conformational change in low pH environment, such as in endosomes. While, there has been many studies done in the past of how this conformational change happens, a recent paper has tried to list the structural and dynamic properties using Molecular Dynamics.
To list these properties,three structures were taken into consideration; one NMR structure (PDB id: 1QLX) and two X-ray structures (PDB id: 2W9E and 3HAK). Interestingly the 3HAK structure is from a SNP variant of human PrPc, where the Met129 is replaced by Val129. Furthermore, those who genetically have this variant are less susceptible to Prion diseases!
Structural alignment of 1QLX (blue), 2W9E (red), and 3HAK (orange) with Met129/Val129 shown as sticks. Image made using PyMOL
Using an in-house MD package called in lucem molecular mechanics, ilmm for short, Chen et al simulated the three structures under two different pH conditions (pH 5 and pH 7) and under two different temperatures (298K/25C and 310K/37C), totaling for about 3.6 microseconds of simulation. (For each structure under each condition the MD simulation was performed in triplicates.)
Analyzing the MD results they found that at 37C and low pH the C-terminal globular domain had significant destabilization effects.
- The helix HA and its neighboring loop S1-HA for the SNP variant was higher compared to other two structures at 37C and low pH. It is interesting to note that the S1-HA loop becomes a strand during the prion’s conversion.
- At low pH, another helix HB destabilizes, where the His187 becomes solvent exposed, leading to partial unfolding of the C-terminus.
- Two residues, Phe198 and Met134, converting from being part of the hydrophobic core to being exposed to the solvent may be involved in partial unfolding and might possibly provide aggregation sites.
- The X-loop in the Val129 SNP variant’s structure took a different conformation that was not populated by the other two structures.
- Formation of new secondary structures of the N-terminus region to either alpha and beta strands is spontaneous. While, in all two structures both alpha and beta strands formation was seen, in the SNP variant alpha strands were rarely formed. (This N-terminus region is missing from the solved structures and hence was modeled and in each starting structure this region was unstructured.)
These results give more insights into the conversion of the benign form of human Prion to the infectious form.
- Chen, W., van der Kamp, M., & Daggett, V. (2014). Structural and Dynamic Properties of the Human Prion Protein Biophysical Journal, 106 (5), 1152-1163 DOI: 10.1016/j.bpj.2013.12.053
I am sure this blog’s readers are aware of the PDB format. This format, created in the 1970s, is a standardized format for data derived from X-ray diffraction and NMR studies . Until 2006, homology/theoretical models were also accepted for deposition, but not any more . [See previous post on Protein Model Portal for submitting homology/theoretical models]
The current limit of PDB format is that a coordinate file with more than 62 chains and 99,999 atoms cannot be uploaded as a single file and hence was split into three or four separate PDB depositions. To overcome this limitation, a new format has been on the works and recently the working group announced the new format recommendations. [3, 4]
Not that I warned you. The first FAQ  on this link says:
What should every PDB user know about PDBx/mmCIF?
The PDB file format will be phased out in 2016.
PDBx/mmCIF will become the standard PDB archive format in 2014.
What is this new format?
To illustrate the changes, the first image is the ATOM records in the current PDB format. And, the second image is the PDBx format of the same information.
The new PDBx format:
Did you observe any changes? Here is a comparative image below that has the ATOM records aligned one below the other.
The first thing that caught my eye was the order of the columns the new format is using. Also, the extra decimal positions for occupancy and B-factor columns. Now, if you look at the second image, we saw some extra lines before the ATOM records. These are the list of things in the “atom_site” category. The new format has the following categories and under each category, there is a detailed description of what goes into it. For example, the ATOM records is what is called as the ATOM_SITE category. Under this, there is information describing atomic positions.
PDB to PDBx correspondences
This link describes what items in PDB correspond to the new PDBx format
The website (http://mmcif.wwpdb.org/) and the FAQ have tons of information. Check it out, and get familiar with the new format of PDB! You have two years to learn it. 🙂
- http://www.rcsb.org/pdb/static.do?p=file_formats/pdb/index.html. Accessed: 2014-03-07. (Archived by WebCite® at http://www.webcitation.org/6NtpuqkvU)
- http://deposit.rcsb.org/depoinfo/depofaq.html. Accessed: 2014-03-07. (Archived by WebCite® at http://www.webcitation.org/6NtpzBByw)
- http://www.emdatabank.org/lrg_strct_dpstn.html. Accessed: 2014-03-07. (Archived by WebCite® at http://www.webcitation.org/6Ntq1KxKY)
- http://www.wwpdb.org/workshop/wgroup.html. Accessed: 2014-03-07. (Archived by WebCite® at http://www.webcitation.org/6Ntq3BY5u)
- http://mmcif.wwpdb.org/docs/faqs/pdbx-mmcif-faq-general.html. Accessed: 2014-03-07. (Archived by WebCite® at http://www.webcitation.org/6Ntq56e1O)