Studies On The Interactions And Proton Transfer Of Biochemical Model Molecules And Small Biomolecules In Solution

Proton transfer is a common and important phenomenon in chemical and biological reactions. Tautomerism of nucleic acid base, which is induced by proton transfer is considered to be one of the origins for the spontaneous point mutation in DNA. As we all know, biomolecules can only properly function in solution, especially in aqueous solution, as a result, when we investigate the proton transfer process of a biomolecule, we must not ignore the effect of the solution surroundings, and that means, we must synchronously study the interactions between the molecules in solution and take them into consideration. Weak interaction plays an essential role in the structures and properties of proteins and nucleic acids as well as in the behavior of many biological systems, and itself is quite an interesting theme for study. In the present work, MD simulation, quantum calculations, NMR experiment are combined to investigate the weak interaction as well as the proton transfer processes of the biochemical model molecules and small biomolecule systems. We will start from the simplest model molecules to the complicated nucleic acid base guanine.Because carbonyl exists in many biomolecules, we first study aqueous solution of acetone, the simplest molecule contains carbonyl. An all-atom acetone model and a TIP5P water model have been adopted for molecular dynamics simulation. We found a weak contact C-H…O between the methyl group next to carbonyl and water. NMR data show good agreement with the hydrogen bonding network. Twoquantitiesη_rel andη_rel^E are applied to study the nonideal association mixture. Westudy the transport properties of the system by comparing theη_rel^E's of strong hydrogen bond and weak contact based on transport properties, MD simulations together with NMR experimental data and find good agreement of concentration dependence, which exhibits the cooperation effect. The solution shows extreme deviation from ideal mixing in the concentration range x_A≈0.3.Formamide, despite its simpleness, it contains the essential features of the peptide linkage and often is used as a model. We study the aqueous solution of formamide as well as its enol form formamidic acid by quantum calculations. It is found that there are three different regions for water molecule to form cluster with the central molecule, one of the clusters contains C-H…O interaction, which is found in acetone aqueous solution, again verified in this mixture by MD simulation. By doing the calculation in the whole concentration, we found that formamide in water-rich region can strengthen the local structure of water, and cross-association between water and formamide will be taken place by the linear association of formamide itself as the concentration of formamide grows higher.After knowing the interaction between formamide and water molecule, we move on to the investigation on its proton transfer process. Water molecules in the vicinity of formamide can be classified into two groups according to the different effects on the proton transfer process of formamide: water in two of them (W1 and W3) can protect formamide from tautomerizing, while in the third one (W2) works oppositely. For a multi-hydrated cluster, it will be an integrated effect of all the hydrated water. Above results are obtained in gas phase as well as in SCIPCM solution model, however, comparing with the situation in gas phase, the protective effects induced by W1 and W3 become smaller, and the assistant effect becomes more obvious. We tried to explain the differentia of the two kinds of water molecule by using the structural variation and potential electronic surface change during the transition, intermolecular interaction between the water and solvent as well as NBO analysis. The same conclusion can be drawn out in the study of Glycinamide, a derivative of formamide, the simplest and appropriate model compound for N-terminal amino acids. At last, a series of small molecules, which can deliver the hydrogen bond in the proton transfer process, are put in the assistant region. Activation energy of the reaction and DPE+PA value of the assistant molecule show a linear relationship, by which we may presume that the assistant molecule get the hydrogen bond from formamide and send out its own hydrogen at the same time in forming the transition state.Guanine is the most sophisticated nucleic acid base. There are 36 possible tautomers, any one of which can be produced by proton transfer from another tautomer. We investigate the complex network by dividing them into seven groups. We found that the relative stability of the tautomers is reasonable both on thermodynamics and dynamics, the unstable tautomer has biggerΔE as well as higher energy barrier in the forming process; reaction direction between two transferable tautomers will be greatly influenced by the geometric property of the remaining part just next to the location where the transition happens; longer proton transfer distance is corresponding to higher activation energy, the vice versa; for transferable isomers with the same framework, keto form is more stable than the enol form, and the amino form is more stable than the imino one, the validity of this conclusion can be checked among the 36 tautomers, and agree with the experiment work. There is a segment quite like formamide in the structure of guanine, so we investigated the water's effect on the tautomerism of 9-H-keto-Guanine, we obtained accordant result: W1 can protect guanine from tautomerizing to the rare enol form, W2 can promote the tautomersim. At last, we study the tautomerization of acetylacetone by NMR, because enol form of this molecule can be actually tested in common surroundings and it does not have the solubility problem, both of which are quite annoying issues for the study of nucleic acid base. To sum up, computer simulation, quantum calculation and experiment are combined to investigate the biochemical model molecules and small biomolecules in solution, some rules on the interaction and the structure variation in solution are discovered. We expect it can provide a base for the future development of the research on the tautomerism of other biomolecules and related gene mutation.