Algorithm Of Dynamic Important Residues Network And Its Application

Protein functions are mostly determined by their three-dimensional structures which linked to conformational changes.Proteins can switch their functional roles among different conformations in response to various environments.Comformation change always companied with the functional process when protein binding agonist or antagonist.Therefore we need to answer two questions in order to undstand the allosteric mechanism,how and why the conformational changes happen.Protein as a macromolecule with diverse spatial structure can undergo flexible and complex conformation change under the force by the interactions from internal residues or external molecules.Protein conformational changes may be caused by reorientations of some residues and torsional changes in the main chain,the changes in torsional angles may induce localized changes or large scale domain motions.Aim to this,we need to investigate the key residues which are responsible for conformational changes and driven forces.First,we found protein conformational changes induced by the character changes of some residues in main chain torsional angles and side chain orientations.Tracing these changes is important for understanding the way of these proteins function.To answer the mentioned question,many computational methods that trace and simulate conformational changes in proteins include Molecular Dynamics(MD),Monte Carlo(MC)and their variants have been released.Additional efficient methods focusing on conformational changes in the protein structures are also employed such as Torsion angle dynamics(TAD),Bee Algorithm,Structured Intuitive Move Selector(SIMS)and Comparison with a classification based on normalized Bfactors.However,traditional biophysics-based conformational search methods require a large number of calculations and are hard to apply to large-scale conformational motions.Here we use Dynamical Importnt Residues Network(DIRN)to identify the character of structural data including Secondary Structure(DSSP),Dihedrals(Dih),Angles of three consecutive amino acids(T-ang),Chi1 torsions(Chi1),Chi2 torsions(Chi2),Chi3 torsions(Chi3),Chi4 torsions(Chi4),Omega torsions(Omega),as well as NMR data such as Scalar Coupling between HN and C_prime(Jnhc),Scalar Coupling between HN and C_beta(Jnhb),Scalar Coupling between HN and H_alpha(Jnha).Second,we study the interactions including hydrogen bond and hydrophobic interaction for these key residues distributing in conformation changing area,finding an obvious interaction network,was mapped on these residues covering global proteins,so we propose a hypothesis that conformational changes are initiated by the variation of interactions through a network comparison of a series key residues and this can also help us undstanding the signaling pathway.Human M2 muscarinic acetylcholine receptor(M2)and opioid receptor kappa(?OR)protein were used to validate this approach.