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E. R. Gaillard, H. Guo, C. Zheng, J. P. Dillon; Computational Simulations on -crystallin Dimers. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4097. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the mechanism of aggregation and determine the regions of interaction along with key residues in the dimerization of alpha-crystallin subunits using computational methods.
The amino acid sequences of homo sapiens alpha-A and alpha-B were obtained from the SWISSPROT database and the sequence similarity was obtained by the global alignment method. The same template was used for both subunits and the preliminary models were obtained by a fold recognition program (3D-PSSM). The initial models were refined using molecular mechanics methods (JACKAL and TINKER) with several force fields. Based on the optimized subunit models, the dimer models were built up with ZDock which utilizes the surface complementary principle. The approach to equilibrium for the dimers over one nanosecond was simulated via Nanoscale Molecular Dynamics (NAMD) and Visual Molecular Dynamics (VMD).
The molecular mechanics optimized models for the alpha-A and alpha-B subunits have RMSD values of 1.02 Å and 1.04 Å, respectively, indicating that the models are very similar to each other. The secondary structure consists of ca. 30% beta-sheet and 15% alpha-helix; the beta-barrel present in these models is consistent with observations that this structural element is highly conserved in members of the small heat shock family of proteins. The ligand docking and dynamic simulations indicate that hydrogen bonds and hydrophobic interactions play very important roles in subunit binding. In addition, the calculated structure shows that the Trp60 residue in the alpha-B subunit is exposed to solvent in the monomer but is buried in the dimer. This and other structural details are in agreement with experimental observations on the photo-oxidation of alpha-crystallin (Finley et al, Photochem Photobiol 1997, 66, 635).
alpha-crystallin is the major structural protein of the mammalian lens and has been shown to exhibit chaperone activity. However, little is known about the tertiary or quarternary structure of the protein. A computational model and dynamics study of the alpha-A/alpha-B dimer is presented and the results are consistent with numerous previously reported experimental observations.
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