Protein Flexibility Analysis (pFlexAna)

Overview

Protein conformational changes play a critical role in vital biological functions. Due to noise in data, deteremining salient conformational changes accurately and efficiently is a challenging problem. We have developed an efficient algorithm for analyzing conformational changes of a protein, given its structures in two different conformations. A key element of the algorithm is a statistical test that determines the similarity of two protein structures in the presence of noise. Using data from the Protein Data Bank and the Macromolecular Movements Database, we tested the algorithm on proteins that exhibit a range of different conformational changes. The results show that our algorithm can reliably detect salient conformational changes, including well-known examples such as hinge and shear.

Protein Conformation Flexibility Analysis

pFlexAna analyzes two protein structures in differing conformations and accurately determines residues involved in conformational change. It's output is a per residue flexibility measure, which also indicates the degree of flexibility in each residue of the protein. The lower this metric, the more flexible the residue.

A salient feature of our method is a principled analysis of statistical noise in structural data, which allows us to reliably distinguish noise from true conformational change. As a result, pFlexAna produces far more accurate results than other methods used to detect conformational changes, as shown in the diagram below. The structure used for this example is the N-lobe of Lactoferrin, which has been shown to undergo hinged conformational changes around residues 90 and 250.

B-factors	Torsion angles	Sliding RMSD

pFlexAna

Using PDB data, we tested our algorithm on proteins exhibiting a wide range of conformational changes - including TBSV Coat Protein, Lactoferrin, Lactate Dehydrogenase, HIV-1 protease, Adenosylcobinamide Kinase and Aspartate transcarbamoylase. Results for these proteins closely match those reported elsewhere in the literature and are shown below.

Software

• The software pFlexAna is an implementation of the algorithm. The source code is availabe for download, and the web server provides direct access to the software.
  source code    documentation    web server

References

• A. Nigham and D. Hsu. Protein Conformational Flexibility Anal ysis with Noisy Data. In Proc. ACM Int. Conf. on Computational Biology (RECOMB), 2007.
  BibTeX   PDF 

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