Normal modes dynamics of multibody proteins: The acetylcholine receptor and its complex with snake toxins
Calculating protein dynamics is essential for a better understanding of many biological processes. To better understand the motion involved in channel opening of the acetylcholine receptor (AChR), I calculated the normal mode dynamics of the AChR (1). The normal modes calculations reveal a twist like gating motion responsible for channel opening. This motion is shown in the movie on the right. Throughout this twist motion, the ion channel diameter is shown to increase. Strikingly, the twist motion and the increase in channel diameter are not observed for the acetylcholine receptor in complex with two α-bungarotoxin (αBTX) molecules. The toxins seem to lock together neighboring receptor subunits thereby inhibiting channel opening. Interestingly, one αBTX molecule is sufficient to prevent the twist motion. These results shed light on the gating mechanism of the acetylcholine receptor, and present a complementary inhibition mechanism by snake venom derived α-neurotoxins. To see more movies of the acetylcholine receptor and its complexes with α-bungarotoxin, click here!
PSF: an online search engine for protein segment motifs in the PDB
To assist the task of finding related conformations in the Protein Data Bank (PDB), I designed a search engine named protein segment finder (PSF) (2). The search engine uses a compact database to quickly identify protein segments obeying a set of primary, secondary and tertiary structure constraints. The database contains information such as amino acid sequence, secondary structure, disulfide bonds, hydrogen bonds, and atoms in contact as calculated from all protein structures in the PDB. The search engine parses the database and returns hits that match the queried parameters. PSF which is notable for its high speed and interactive feedback, is expected to assist scientists in discovering conformation homologs and predicting protein structure. PSF is publicly available online at http://ari.stanford.edu/psf
Modeling of Protein Structure: The surface protein gp120 of the HIV virus
Much information and insigth at atomic resoltion can be gained from the 3D structure of protein models. Recently, I constructed a model of the gp120 of R5 HIV with the hypervariable V3 loop using homology modeling. The model is based on NMR data for the V3 loop and the crystal structure of the gp120-core. The model is also based on interactions revealed by sequence analysis, i.e. the correlated mutations at positions 322 and 440, suggesting that these two residues interact closely. This model contributes to our understanding of biological phenotype conversion of HIV (3).
Prediction of residue pairing in &beta-sheets
Amino acid propensities for α-helix and β-sheet formation have long been known. Recently, I calculated the propensities of residue pairing in β-structure (unpublished results). This propensity is capable of predicting pairing of residues across &beta-sheets as well as β-bulges.
1. Samson, A. O. & Levitt, M. (2008). Inhibition mechanism of the acetylcholine receptor by α-neurotoxins as revealed by normal-mode dynamics. Biochemistry 47, 4065-70.
2. Samson, A. O. & Levitt, M. (2009). Protein segment finder: an online search engine for segment motifs in the PDB. Nucleic Acids Res 37, D224-8.
3. Rosen, O., Samson, A. O. & Anglister, J. (2008). Correlated mutations at gp120 positions 322 and 440: implications for gp120 structure. Proteins 71, 1066-70.