Browsing by Author "Best, Robert"

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    Addition of flexible linkers to GPU-accelerated coarse-grained simulations of protein-protein docking
    (2019) Pinska, Adrianna; Kuttel, Michelle; Gain, James; Best, Robert
    Multiprotein complexes are responsible for many vital cellular functions, and understanding their formation has many applications in medical research. Computer simulation has become a valuable tool in the study of biochemical processes, but simulation of large molecular structures such as proteins on a useful scale is computationally expensive. A compromise must be made between the level of detail at which a simulation can be performed, the size of the structures which can be modelled and the time scale of the simulation. Techniques which can be used to reduce the cost of such simulations include the use of coarse-grained models and parallelisation of the code. Parallelisation has recently been made more accessible by the advent of Graphics Processing Units (GPUs), a consumer technology which has become an affordable alternative to more specialised parallel hardware. We extend an existing implementation of a Monte Carlo protein-protein docking simulation using the Kim and Hummer coarse-grained protein model [1] on a heterogeneous GPU-CPU architecture [2]. This implementation has achieved a significant speed-up over previous serial implementations as a result of the efficient parallelisation of its expensive non-bonded potential energy calculation on the GPU. Our contribution is the addition of the optional capability for modelling flexible linkers between rigid domains of a single protein. We implement additional Monte Carlo mutations to allow for movement of residues within linkers, and for movement of domains connected by a linker with respect to each other. We also add potential terms for pseudo-bonds, pseudo-angles and pseudo-torsions between residues to the potential calculation, and include additional residue pairs in the non-bonded potential sum. Our flexible linker code has been tested, validated and benchmarked. We find that the implementation is correct, and that the addition of the linkers does not significantly impact the performance of the simulation. This modification may be used to enable fast simulation of the interaction between component proteins in a multiprotein complex, in configurations which are constrained to preserve particular linkages between the proteins. We demonstrate this utility with a series of simulations of diubiquitin chains, comparing the structure of chains formed through all known linkages between two ubiquitin monomers. We find reasonable agreement between our simulated structures and experimental data on the characteristics of diubiquitin chains in solution.
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    Combined NMR and simulation study of carbohydrate linkage dynamics
    (2000) Best, Robert; Naidoo, Kevin; Jackson, Graham Ellis
    Biomaterials have recently gained significance as a result of environmental pressures and their increased viability through crop engineering. Starch harvested from maize crops is one example of a cheap and abundant biopolymer, which could substitute conventional polymers such as polyethylene as a material in manufacturing. Its practical application, however, will depend on understanding its physical behaviour, so that intelligent modifications can be made to enhance its properties. The most effective way of changing a polymer's properties is by modification at the chemical level, since ultimately it is this which determines the macroscopic features, such as viscosity, plasticity and tensile strength. Since the origin of these features is difficult to study experimentally, this thesis will tackle the problem by means of computer simulation of small carbohydrate fragments. In particular, the two principal types of carbohydra te linkage (namely 0: (1--+4) and 0: (1--+6)) will be examined in this thesis, since these are the chief elements of conformational flexibility in these molecules. The 0(1--+4) and 0:(1--+6) linkages are studied both separately in the maltose and isomaltose molecules respectively and together in panose and the resultant water structuring and dynamic behaviour are studied. Although the computational approach provides insights not available experimentally, it is nonetheless important to compare the results obtained with an experimental reference as a check on their validity. N!vlR T1 relaxation measurements, which give indirect information on the atomic scale dynamics, have been measured for each of the model fragments and compared with values calculated directly from simulation.