Computational Study On The Effects Of Non-covalent Interactions On The Structures And Stabilities Of Large Molecules

Non-covalent interactions are ubiquitous in nature. The study of the non-covalent interactions results in the creation of novel subjects, such as supramolecular chemistry. There are a huge quantity of chemical processes involving non-covalent interactions, such as catalysis, drug synthesis, molecular recognition, and self-assembly. Experimental studies have revealed that the modulation of non-covalent interactions can result in numerous chemical phenomena. However, most of them have not been rationalized at molecular or electronic level. On the other hand, due to the rapid development of theoretical chemistry and computer science, computational chemists can now carry out quantum mechanical calculations to study the effect of non-covalent interactions. But these computational efforts are still limited, compared to tremendous experimental efforts.As the systems involved in experiments are relatively large, the density functional theory (DFT) becomes the first choice in quantum chemistry calculations. DFT methods are not only computationally cost-effective, but also can provide reasonably accurate results if appropriate functionals are chosen. On the other hand, ab initio correlation methods are able to give highly accurate results, but their computational costs are generally too high for large molecules. Since there are a large number of density functionals available in literatures, selection of suitable functionals for systems under study is very critical to get reliable results. The main task of this thesis is to (1) evaluate the performance of a number of density functionals in describing the intramolecular dispersion interaction;(2) to investigate how the intra-molecular dispersion interaction and hydrogen bonding interactions affect the structures and stabilities of large polypeptides. The main work in the present thesis can be summarized as follows:1. In chapter3, we assessed the performance of a number of density functionals in describing the intramolecular dispersion interaction through studying the conformational energy differences between the all-gauche and all-trans conformers for several large normal alkanes. With the generalized energy-based fragmentation (GEBF) approach, we obtained the conformational energy differences at the CCSD(T) level, which are selected to be the reference data. The calculated results show that (1) The M06-2X functional has the best performance, followed by MPWB1K. Other functionals severely overestimate the conformational energy differences.(2) The addition of a Grimme’s DFT-D3dispersion correction to the functionals offers considerable improvement on the performance of these functionals. Especially, the LC-wPBE-D3functional show comparable performance as the M06-2X functional. Our results suggest that the functional M06-2X is appropriate for studying large molecules with significant dispersion interactions.2. In chapter4, we have investigated the structures and stabilities of five typical conformations for five16-residue polypeptides with full quantum mechanical calculations. The polypeptides under study are based only glycine and alanine residues, which include AcA15K, Ac(AGG)5K, AcG15K, AcG6A3G6K and AcG3AG5AG4AK (Ac=acetyl, G=glycine, A=alanine, K=Lysine). The GEBF approach within the framework of the M06-2X functional (abbreviated as GEBF-M06-2X) is employed to perform full quantum mechanical calculations on selected systems. Among five conformations of each polypeptide,310-helix is the thermodynamically most stable conformation in free energy (except for AcG15K), and the globular conformation is the most stable for AcG15K. For systems AcG15K, Ac(AGG)5K, and AcA15K, with the increase of the ratio of alanine to glycine residues, the helix-formation propensity of polypeptides in gas phase increases gradually. For AcG6A3G6K and AcG3AG5AG4AK, which have different distribution of alanine residues, AcG3AG5AG4AK (with more uniform distribution) possesses a larger helical propensity than AcG6A3G6K. The low-cost DFTB (density functional based tight binding) and Charmm22force field methods cannot give reasonably accurate descriptions on conformational energy differences of large polypeptides.3.In chapter5, by combining the molecular dynamics simulations with density functional theory calculations, we studied the low-lying structures of both unnatural hybrid octapeptides in crystal environment and in gas environment. The two selected unnatural polypeptides are Boc-[Aib-β3(R)Val]4-OMe and Boc-[Aib-a(S)Val]4-OMe. For both systems, the calculated results show that the lowest-energy conformer is hybrid helical structure, not pure a-helix-like or310-helix-like one. For Boc-[Aib-β3(R)Val]4-OMe, our calculations show that the corresponding infinite polypeptide has an a-helix-like structure as the most stable structure. This result is in accord with the experimental crystal structure. For Boc-[Aib-a(S)Val]4-OMe, our calculations show that the infinite polypeptide will exist in310-helix-like structure, which is also consistent with the observed crystal structure. The present study demonstrates that the peptide conformer in the crystal environment does not necessarily correspond to the most stable structure in vacuum.