The computational investigation of conformational change

Abstract

Methods for investigating conformational motions are developed and applied to a range of protein systems. The motions of biological molecules can occur on timescales beyond that accessible to molecular dynamics (MD) simulation, and algorithms that enhance conformational sampling are therefore of great use. Reversible digitally filtered molecular dynamics (RDFMD) can amplify or suppress motions of specific frequencies as a simulation evolves. A method for the systematic parameterisation of RDFMD is presented and used to generate a protocol that maximises backbone dihedral angle change without overheating the target system. The recently developed Hilbert-Huang transform (HHT) is used to determine the most suitable frequencies for amplification by RDFMD. A computational expensive parallel tempering (PT) simulation has been performed on the YPGDV pentapeptide, to determine the equilibrium distribution of accessible conformers. This has then been used to assist in the parameterisation of the RDFMD method. PT of YPGDV has also been used to study the population of cis and trans peptide bonds at a range of temperatures, sampling almost three thousand isomerisation events. Investigations into the conformational motions of T4 lysozyme, E. coli dihydrofolate reductase (EcDHFR), and a human immunodeficiency virus-1 protease (HIV-1 PR) are also presented. In each case, conclusions from MD, PT and RDFMD are in agreement with experimental data, and provide further insight into the dynamics of the system.

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