INPhINIT Incoming Fellowship – Identifying function of non-structured proteins by molecular simulations. New paradigm for intrinsic disordered proteins.
s.madurga@ub.edu
RESEARCH PRODUCT / RESEARCH GROUP
The investigation of intrinsically disordered proteins (IDPs) is a new challenge in structural and molecular biology that requires a new paradigm to decipher how structural disorder is translated into biological function. Intrinsically disordered proteins (IDPs) are a class of proteins that are not able to fold into well-defined three-dimensional structures. There is an increasing interest in IDPs because now it is known that IDPs represent a significant fraction of the human proteome, about half of the proteins in eukaryotes. The classical structure-function paradigm that has successfully been used for understanding molecular biology breaks down when considering proteins that have no stable tertiary structure in their functional form. Thus, it is needed to develop a new strategy to determine the function of IDPs. Because these molecules have a combination of acid/base residues, their conformational properties are strongly coupled to the pH of the medium. Thus, to be able to study their properties we will develop a new strategy using constant pH molecular dynamics methods.
In this project, molecular dynamics simulations and statistical thermodynamics will be used to characterize at atomic-level this paramount class of proteins. In the developed methodology, protein structure and function should be strongly dependent on solvent pH. This dependence is due to changes in the predominant protonation state of titrable groups as solvent pH changes. In particular, using atomistic simulations will be studied the determination of radii of gyration, as a parameter that characterizes the ensemble of conformations; it will be analyzed the effect of ratio and position of hydrophobic and hydrophilic residues; and finally, it will be investigated the role of global charge, charge distribution and effect with respect to the pH. To investigate this effect, state-of-the-art molecular dynamic simulations and Semi Grand Canonical Monte Carlo (SGCMC) simulations at constant pH will be used.
The PhD candidate will be incorporated into the “Theoretical and Computational Chemistry” doctorate program of the University of Barcelona, which belongs to the European Join Doctorate on “Theoretical Chemistry and Computation Modelling”.
The candidates must have a minimum of 300 ECTS (European Chemistry Transfer System), with a minimum of 180 degree ECTS related to Physics, Chemistry, Biochemistry or Biomedical, Chemical or Materials Engineering, and a minimum of 60 Master ECTS related to the same degrees or with Computational Sciences, Biophysics or Bioinformatics.
The development of the PhD would be organized in order that the candidate has the possibility to obtain the “International Mention”:
http://www.ub.edu/escola_doctorat/en/academicinformation/international-mention
He/she will belong to the Doctorate School of Barcelona University.
The PhD will be developed in the Theoretical and Computational Chemistry Research Institute of the Barcelona University (IQTCUB) with the informatics cluster resources that the BioPhysChem group has accessibility. Moreover, the BioPhysChem group belongs to the Reference Network of Theoretical and Computational Chemistry of Catalonia, which will bring the opportunity to the candidate to participate in conferences and workshops with different groups of Catalonia and share the experiences of different research groups with similar interests. In particular, there will be the possibility to interact with other computational and experimental groups in the Barcelona area who develop research in areas related to IDPs. Finally, there will also be the possibility to perform several stages on some foreign well-recognized research groups.
OTHER RELEVANT WEBSITES
This website corresponds to a special issue of Chemical Reviews of 2014 devoted to the study and applications of the intrinsically disordered proteins (IDPs). This thematic issue provides a collection of focused articles in the field of IDPs. These articles are not simply reviews, but they contain new interpretations and opinions of authors. Obviously, not all-important aspects are covered, and this collection of reviews is meant to serve as a starting point for future discussions of this intriguing phenomenon. In fact, contrarily to the ordered proteins and domains, such biologically active intrinsically disordered proteins (IDPs) and intrinsically disordered protein regions (IDPRs) have no single, well-defined equilibrium structure and exist as highly dynamic, heterogeneous ensembles of conformers resulting from their relatively flat free-energy surface. The rapidly growing interest in IDPs can be attributed to several factors. The first of them is the role these proteins play in changing the understanding of the molecular mechanisms of protein action and in reshaping the protein structure–function relationship. The discovery of biologically active but extremely flexible proteins questioned the assumption that unique 3D structure is a prerequisite for protein function. Although IDPs lack stable structures at functional conditions, they are known to carry out a number of crucial biological functions that are complementary to the functional repertoire of structured (ordered) proteins. In any given organism, IDPs constitute a functionally broad and densely populated subset of its proteome. The overall biological importance of IDPs/IDPRs, and their crucial roles in many biological processes, are further supported by the evolutionary persistence of these proteins and regions. IDPs are common across the three domains of life, being especially abundant in the eukaryotic proteomes.