Fehérjék 3. Simon István

p27 Kip1 IA 3 FnBP Tcf3 Bound IUP structures

A1 A2 D Bound IUPs – conformations

IUPs – preformed elements

1.Dunker order promoting: W, C, F, I, Y, V, L, N disorder promoting: K, E, P, S, Q, G, R, G, A 2. Uversky High net charge/ low average hydrophobicity 3.Machine learning algorithms (SVM, NN) Datasets PDB for ordered short and long disorder Prediction of protein disorder from the amino acid sequence Prediction of protein disorder from the amino acid sequence

Pairwise energy calculated from structure

To take into account that the contribution of amino acid i depends on its interaction partners, we need a quadratic form in the amino acid composition The connection between composition and energy is encoded by the 20x20 energy predictor matrix: P ij Estimation of pairwise energies from amino acid compositions

Estimated energies correlate with calculated energies Corr coeff: 0.74

Estimated pairwise energies of globular proteins and IUPs IUPs Glob

Predicting protein disorder - IUPred Basic idea: If a residue is surrounded by other residues such that they cannot form enough favorable contacts, it will not adopt a well defined structureit will be disordered …..QSDPSVEPPLSQETFSDLWKLLPENNVLSPLPSQAMDDLMLSPDDIEQWFTEDPGPDEAPRMPEAAPRVAPAPAAPTPAAPAPA….. Amino acid composition of environ- ment: A – 10% C – 0% D – 12 % E – 10 % F – 2 % etc… Estimate the interaction energy between the residue and its sequential environment Decide the probability of the residue being disordered based on this The algorithm:

Globular proteins are not representative of full genomes Probable IUPs GLOB Human genome TM ?

IUPs: high frequency in proteomes coli yeast

Erdős-Rényi The yeast interactome Barabási-Albert Networks

LM – average disorder profiles local drop in disorder

Distinct interfaces of disordered proteins More hydrophobic More hydrophobic More residue-residue contacts More residue-residue contacts Less segments Less segments