Force fields for biomolecular simulations: from supra-molecular bio-inspired catalysts to protein- inhibitors complexes
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Date
18/03/2022Author
Bariami, Sofia
Metadata
Abstract
Over the past decades, molecular modelling and molecular dynamics
(MD) simulations have become well- established disciplines, providing special
tools for the study of chemical and biological processes. To perform
classical MD simulations, a clear description of the connectivity and the
electrostatic behaviour of the system is required. This is done with the use
of Force Fields (FF), sets of parameters and functions, which allow the calculation
of the potential energy of the molecular system of interest. The work
in this thesis demonstrates the development of FF parameters and computational
methods to model and analyse molecular systems that vary from
supra-molecular host-guest complexes to protein -inhibitor systems.
The supra- molecular nano- capsule under study consists of four 3- pyridine
ditopic organic ligands bridged together with two Pd2+ ions and it
shows catalytic activity. Initially, parameterisation of the molecular building
blocks of the system (Pd2+, host ligands, guest molecules, solvent and
counter-ions) was conducted using the OPLS-AA FF and the paremeters
were validated against experimental data. Then, alchemical free energy calculations
were run to estimate the absolute binding free energies for a set
of seven guest molecules to the host using the Sire OpenMM Molecular Dynamics
(SOMD) software of the Sire MD Framework. The results were then
compared with available experimental binding affinity data. The initial runs
using the OPLS-AA non-polarisable FF, failed to reproduce the experimental
trends. However, after modifications were introduced to the charges of
the guest molecules, the calculated binding free energies managed to reproduce
the experimental trends. The most striking observation to emerge from
this study is the importance of the quality of the FF parameters to accurately
describe a molecular system and predict its properties.
The need for an accurate description of the system under study, has
pushed the scientific community into developing FFs that are system- bespoke,
such as the QUBE FF, which derives parameters solely from Qunatum
Mechanical (QM) calculations. The aim of my work is to modify the
source code of Sire MD framework, to allow the incorporation of the QUBE
FF for alchemical free energy calculations. New features, such as inclusion
of the geometric combining rules and XML file parsing were incorporated
using Python and C++ programming languages. The implementation
was tested by calculating Hydration Free Energies (HFE) for a set of small
molecules using SOMD. The results were in agreement with HFE calculated
with the GROMACS MD package (MAE = 0.15 kcal/mol). Furthermore,
relative binding free energy calculations were conducted, for HIV-Reverse
Transcriptase (HIV-RT), and two sets of its inhibitors. Both the enzyme and
the ligands were parameterised using the QUBE and the Amber FFs and
the results were compared with available pEC50 data. Both FFs managed
to reproduce experimental trends, however the performance of the FFs was
found to depend on the molecule under study. Nonetheless, integrating the
QUBE FF into the Sire MD framework provides a stable, adaptable platform
with GPU-accelerated dynamics, which can significantly increase our
ability to evaluate and apply customised QM-derived parameters for drug
design.
To further improve the accuracy of the QUBE FF, off-center charges (virtual
sites) were introduced to account for polarisability effects. Functionality
in Sire was further extended to include virtual sites in MD simulations,
which are also supported by the QUBE FF. The new feature of Sire
was tested by calculating Single Point Energies (SPEs) and HFEs for a set
of small molecules and comparing them with available experimental data.
Finally, the induced myeloid leukemia cell differentiation protein (Mcl-1)
and a set of its inhibitors were parameterised using the new QUBE FF that
includes virtual sites. Absolute and relative binding free energy calculations
were conducted and compared with results from previous studies
which use the Amber FF, as well as with experimental assays. Both Amber
and QUBE were found to overestimate the binding strength of the three
inhibitors (MAEQUBE = 4.74 kcal/mol, MAEAmber = 4.15 kcal/mol). This
discrepancy from the experimental data was attributed to the vdW interactions
between the ligand and the hydrophobic binding pocket of the protein.
Analysis of the RBFE results revealed that Amber outperformed QUBE
with VS inclusion (MAEQUBE = 0.91 kcal/mol, MAEAmber = 0.75 kcal/mol).
However, the evidence from this study suggests that alchemical free energy
calculations which model anisotropy can be conducted accurately and fast
with SOMD, providing another useful tool to the scientific community for
drug design purposes.