De Novo Generation of Bound Structures for an Intrinsically Disordered Protein using Only Alpha Carbon Chemical Shifts

Abstract

Intrinsically disordered proteins (IDPs) challenge our traditional notions of protein structure/function relationships because they are highly dynamic in their native state and do not form tertiary structures. To design new drugs for IDPs it is essential to generate realistic structural ensembles for these proteins. We have recently developed a method called broad ensemble generation with re-weighting (BEGR) where a million or more diverse IDP structures are generated and then re-weighted to fit experimental data. Results show that bound state structures of the disordered p53 transactivation domain (p53TAD) are reproducibly generated, even though the BEGR method is using experimental data for unbound p53TAD. These bound state structures were found for wild type p53TAD and a mutant that increases the transient helical secondary structure of one of the binding sites using only the alpha carbon chemical shift data.