||<p>Molecular dynamics (MD) simulations is an invaluable tool to investigate chemical
and biological processes in atomic details. The accuracy of MD simulations strongly
depends on underlying force fields. In conventional molecular mechanics (MM) force
fields, the total energy is divided into bond energy, angle energy, dihedral energy,
electrostatic interactions and van der Waals interactions. Each of these energy terms
is parameterized by fitting to either experimental data or quantum mechanical (QM)
calculations. In this dissertation, our aim is to develop accurate force fields for
small molecules, water and proteins fully from QM calculations of small fragments.
In the framework of conventional MM force fields, we calculated both transferable
and molecule-specific atomic polarizabilities of small molecules by electrostatic
potential fitting. Atomic polarizabilities are the key physical quantities in induced
dipole polarization model. Molecular polarizabilities recovered from our atomic polarizabilities
show good agreement with those obtained from QM calculations. We believe the main
limitation of conventional MM force fields is the limited form of its Hamiltonian.
Going beyond conventional MM force fields, we adopt the many-body expansion method
and residue-based systematic molecular fragmentation (rSMF) method to start afresh
building force fields for water and proteins, respectively. We used electrostatically
embedded two-body expansion as the Hamiltonian of bulk water. QM reference of electrostatically
embedded water monomer and dimer at the level of CCSD/aug-cc-pVDZ are parameterized
by neural network (NN). Compared with experimental results, our water force fields
show good structural and dynamical properties of bulk water. We developed rSMF to
partition general proteins into twenty amino acid dipeptides and one peptide bond.
The total energy of proteins is the combination of the energy of these small fragments.
The QM reference energy of each fragment is parameterized by NN. Our protein force
fields compare favorably with full QM calculations for both homogeneous and heterogeneous
polypeptides in terms of energy and force errors.</p>