Molecular Modeling of N-glycosylation on Proteins' Structures and Functions

The works in this thesis are mainly dealing with computational molecular modeling applied to biomolecular systems. It includes three projects, and the project one is my most important work.;In the first project, Molecular Dynamics (MD) is used to understand the N-glycosylation and its affects on structures and functions of glycoproteins. N-glycosylation is one of the most common co-translational and post-translational modifications occurring in protein. CD2 is one important transmembrane cell surface glycoprotein found on T lymphocytes and natural killer cells. The N-glycosylation presented on human CD2 plays critical role for the adhesion function, while the rat CD2 doesn't need glycan for its normal functions. Our study revealed that N-glycosylation of human CD2 at the type I β–bulge turn strengthens the relevant hydrogen bonds, which make the glycosylation loop more rigid comparing to its nonglycosylated counterpart. Furthermore, the glycosylation is essential in modulating human CD2's conformational ensemble. After glycosylation, the conformational ensemble of human CD2 is drifted toward a more suitable conformation for binding CD58. This theoretical result is in excellent agreement with previous experiments and may give us a better understanding on how the glycosylation governs protein's structures and functions.;In my second project, MD simulations were carried out to study helix-helix interaction using both standard AMBER and polarized force fields. The helix dimer (GpA) was more stable when the electrostatic polarization effect was included. This study should help shed light on the importance of electrostatic polarization of protein in helix-helix interaction and helix bundle structures.;Finally, main chain torsions of a model peptide was parameterized into a 2-dimensional Fourier expansion based on quantum mechanical calculation at M06 2X/aug-cc-pvtz/HF/6-31G** level in my last project. With this new main chain torsion terms, we studied the main chain dihedral distributions of ALA dipeptide and pentapeptide. The result demonstrated that 2D main chain torsion is effective in delineating the energy variation associated with rotations along main chain dihedrals. This work also serves as an implication for the necessity of more accurate description of main chain torsions in the future development of force field functional forms.