Seeing Double
Our recent analysis of the hundreds of thousands of crystal structures deposited in the Protein Data Bank has identified protein backbone segments modelled in alternate conformations. We used molecular dynamics simulations to identify the cases where these dual conformations maintain increased intrinsic stability. The figure on the right shows such a case (PDB code: 4OLE). Alternate conformations shown in blue and red were simulated individually and remained stable over the duration of the simulations. We are now characterizing the nature of these protein segments, the mechanism(s) behind their formation and how this phenomenon affects protein function. We are also interested in using these experimentally determined cases of alternate conformations to improve prediction of protein structural ensembles. Addressing our goals will contribute to paving the path towards a clearer view of the emerging consensus in structural biology that one sequence translates and folds into many structures.
Amino Domino
Proteins fold from chains of amino acids, forming secondary structures, α-helices and β-strands, that subsequently fold into a three-dimensional structure. Based on our large-scale analysis of high-resolution protein structures, we suggest an "amino-domino" model that describes amino acid pairs as structural elements defined by only two dihedral angles, those separated by the peptide bond, specifically ψ of the first amino acid and φ of the second. Based on this model we have shown that single point mutations in GFP are sensitive to the identity of the adjacent residues in the amino acid chain in a manner which is predictable by comparison of the dihedral angle distributions of the relevant amino acid pairs. We believe the amino-domino model will find use in protein engineering and are now investigating this concept in additional proteins and assessing the additivity of stability introduced by such mutations.
