Polypeptide folding on a conformational‐space network: Dependence of network topology on the structural discretization procedure

Mapping the conformational space of a polypeptide onto a network of conformational states involves a number of subjective choices, mostly in relation to the definition of conformation and its discrete nature in a network framework. Here, we evaluate the robustness of the topology of conformational‐space networks derived from Molecular Dynamics (MD) simulations with respect to the use of different discretization (clustering) methods, variation of their parameters, simulation length and analysis time‐step, and removing high‐frequency motions from the coordinate trajectories. In addition, we investigate the extent to which polypeptide dynamics can be reproduced on the resulting networks when assuming Markovian behavior. The analysis is based on eight 500 ns and eight 400 ns MD simulations in explicit water of two 10‐residue peptides. Three clustering algorithms were used, two of them based on the pair‐wise root‐mean‐square difference between structures and one on dihedral‐angle patterns. A short characteristic path length and a power‐law behavior of the probability distribution of the node degree are obtained irrespective of the clustering method or the value of any of the tested parameters. The average cliquishness is consistently one or two orders of magnitude larger than that of a random realization of a network of corresponding size and connectivity. The cliquishness as function of node degree and the kinetic properties of the networks are found to be most dependent on clustering method and/or parameters. Although Markovian simulations on the networks reproduce cluster populations accurately, their kinetic properties most often differ from those observed in the MD simulations. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010