Frustration and Energetics in the Ankyrin Repeat Protein Fold

PARRA RODRIGO GONZALO; ROCIO ESPADA; NINA VERSTRAETE; DIEGO ULISES FERREIRO

Bariloche

Congreso; 5to Congreso Argentino de Bioinformatica y Biologia Computacional; 2014

Asociacion Argentina de Bioinformatica y Biologia Computacional

Background. Natural protein sequences resemble random strings of amino acids. Patterns of a relatively small set of folding architectures can be characterized by long distance interactions among amino acids. Repeat proteins are composed of tandem copies of similar motifs and can get spontaneously organized in symmetrical ways in space. Ankyrin repeat proteins comprise a large number of proteins containing tandem copies of a 33 residues length motif. They are present in all kingdoms of life, and are apparently enriched in eukaryotes and some specific pathogens. Quasi one-dimensional, these proteins constitute a simplified model, where the ?sequence-codes-structure-codes-function? paradigm can be quantitative evaluated. Description. Given a structural detection of repeats we have achieved in a previous work using a geometrical approach we developed [1], we analyzed the local frustration and energetic patterns of ankyrin repeat proteins in order to dissect the energetical contributions corresponding to the different repeats, the array of repeats and their modifications. We have quantified the degree of conservation of the frustrated state over the canonical positions of the ankyrin repeats as well as for the different contacts that are present in the canonical contact map. Here we describe how frustration patterns are distributed on the structures of this protein family and how it is related with other structural and sequence measures that were calculated over the dataset. Results. We have analyzed the energetical and frustration patterns in the ankyrin repeat protein structures. Natural ankryin proteins are composed of three different populations of repeats that differ in their burial interaction energies that is also reflected in differential sequence signatures and secondary structure composition. We found that these molecules have frustration hotspots that are localized at the insertions and at binding sites for other partners as well as in the terminal repeats. When quantifying the degree of conservation of the frustrated states at the level of canonical positions in the ankyrin repeats we observed that those positions that are conserved correspond to positions where the sequence is also conserved. Moreover, when the frustrated state is conserved, it corresponds to the minimally frustrated one, i.e, ?the more consensus an ankyrin protein is, the more foldable it is?. These positions that have high conservation of the frustrated state at the single residue level are connected by a minimally frustrated interaction network. We speculate that, at least in ankyrin repeats, consensus sequences stabilize the overall fold by maximying the energetic gap between the folded and unfolded states establishing a network of minimally frustrated interactions both within and between adjacent repeats. The potential implicancies of these findings for the dynamical protepties of these molecules will also be discussed. References 1. R. Gonzalo Parra , Rocío Espada , Ignacio E. Sanchez , Manfred J. Sippl , and Diego U. Ferreiro. ?Detecting repetitions and periodicities in proteins by tiling the structural space .? J. Phys. Chem. B. DOI: 10.1021/jp402105j. Publication Date (Web): 11 Jun 2013.