The study of conformational motions using enhanced sampling techniques

Abstract

Computational methods are used for the study of conformational change in biological molecules. Conventional molecular dynamics (MD) has been shown to frequently fail to sample the long timescales over which many biological processes occur, and numerous methods have been developed to overcome this problem. In this thesis, two such methods, in addition to MD, are used to study the conformational of biological molecules. The enhanced sampling method of parallel tempering (PT) is used to investigate the trans-cis isomerisation of peptide bonds in two small cyclic peptide systems, and reversible digitally filtered molecular dynamics (RDFMD), a method which enhances conformational dynamics by selectively enhancing or suppressing the vibrational motion of specific regions of interest in molecules, is used to investigate the effects on conformation as a result of mutation in the HIV-1 enzymes, HIV-1 protease (HIV-1 PR) and HIV-1 integrase (HIV-1 IN) in the apo state. Additionally, the method has been used to investigate the effect of mutation on the conformational dynamics when HIV-1 PR is bound to inhibitors.

In simulations where the enhanced sampling methods of PT and RDFMD have been applied in this thesis, increased conformational sampling compared with MD simulations has been observed. PT simulations are found to be computationally expensive and perhaps unsuitable for application to large protein systems. The RDFMD simulations are able to efficiently accelerate infrequent large-scale conformational changes, thereby revealing new conformations which were not present in simulations carried out using conventional MD, and provide a greater understanding of the mechanism and the effect of mutation on the HIV-1 PR and HIV-1 IN enzymes.

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