Understanding structural features of biomolecular interactions : from classical simulations to ab initio calculations
The structures of biomolecules and their interactions dictate their functions. In this thesis, five papers are presented to illustrate how the dynamics of biomolecules can be investigated and derivation of desired thermodynamic quantities obtained by utilising a diverse range of computational...
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Format: | Theses and Dissertations |
Language: | English |
Published: |
2017
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Online Access: | http://hdl.handle.net/10356/72892 |
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Institution: | Nanyang Technological University |
Language: | English |
Summary: | The structures of biomolecules and their interactions dictate their functions. In this thesis, five
papers are presented to illustrate how the dynamics of biomolecules can be investigated and
derivation of desired thermodynamic quantities obtained by utilising a diverse range of
computational techniques, from simulations utilising classical mechanical descriptions to
calculations employing quantum mechanical descriptions.
Classical simulation, referring to molecular dynamics simulation with atomistic force fields,
has been used in every paper in this thesis. In Paper I, classical simulation and homology
modelling are used to investigate the dynamics of a protein as well as that of its homologues,
which have a missing region. Protein purification and production of these homologues was
also attempted.
When state transitions like protonation and tautomerisation equilibria are central to the query,
we employed lambda-dynamics, an extension to conventional simulation that can describe
transitions between states by including coupling parameter lambda in the dynamics. In Papers
II and III, protonation and tautomerisation equilibria respectively are central to the query.
In Paper II, lambda-dynamics and multiple pH regime are both used to calculate the pK shifts
of cytidine in triplex nucleic acid environments. In some of the triplex nucleic acid systems,
sugar modification LNA is present. The force field parameters of LNA have been updated to
provider better descriptions for pK calculations. In Paper III, lambda-dynamics is used to
describe tautomerisation equilibrium between two tautomers of pseudoisocytidine in singlestranded and triple-stranded nucleic acids in order to observe how the equilibrium shifts in
different environments. In vitro binding assay is used to corroborate the computational
results.
When greater accuracy for certain properties like electrostatics or energetics is required, we
employed quantum mechanical calculations as well as hybrid methods which combine
classical and quantum mechanical descriptions. In Paper IV, QM and QM/MM calculations
were performed to calculate the energetic difference between two tautomers in the ribosome.
In Paper V, protein-specific polarised charge, a charge update scheme that updates the atomic
charges with QM and Poisson-Boltzmann calculations during classical simulation, is used for
better electrostatics description of a peptide. |
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