Development and application of an enhanced sampling molecular dynamics method to the conformational exploration of biologically relevant molecules

This thesis describes the development a new swarm-enhanced sampling methodology and its application to the exploration of biologically relevant molecules. First, the development of a new multi-dimensional swarm-enhanced sampling molecular dynamics (msesMD) approach is detailed. Relative to the original swarm-enhanced sampling molecular dynamics (sesMD) methodology, the msesMD method demonstrates improved parameter transferability, resulting in more extensive sampling when scaling to larger systems such as alanine heptapeptide. The implementation and optimisation of the swarm-enhanced sampling algorithms in the AMBER software suite are also described. Through the use of the newer pmemd molecular dynamics (MD) engine and asynchronous MPI routines, speedups of up to three times the original sesMD implementation were achieved. The msesMD method is then applied to the investigation of carbohydrates, first looking at rare conformational changes in Lewis oligosaccharides. Validating against multi-microsecond unbiased MD trajectories and other enhanced sampling methods, the msesMD simulations identified rare conformational changes leading to the adoption of non-canonical unstacked core trisaccharide structures. Next, the use of msesMD as a tool to probe pyranose ring pucker events is explored. Evaluating against four benchmark monosaccharide systems, msesMD simulations accurately recover puckering details not easily obtained via multi-microsecond unbiased MD. This was followed by an exploration of the impact of ring substituents on conformation in glycosaminoglycan monosaccharides: through msesMD simulations, the influence of specific sulfation patterns were explored, finding that in some cases, such as 4-O-sulfation in N-acetyl-galactosamine, large changes in the relative stability of ring conformers can arise. Finally, the msesMD method was coupled with a thermodynamic integration scheme and used to evaluate solvation free energies for small molecule systems. Comparing against independent trajectory TI simulations, it was found that although the correct solvation free energies were obtained, the msesMD based method did not offer an advantage over unbiased MD for these small molecule systems. However, interesting discrepancies in free energy estimates arising from the use of hydrogen mass repartitioning were found.