Probing Hydrogen Bonds in Aqueous and Biological Systems: Solvation Structure, Dynamics and Spectroscopy

Abstract

Hydrogen bonding interactions are arguably one of the most important interactions in chemical and biological systems, determining the structure and properties of aqueous solutions, assisting the recognition of ligands by proteins, and facilitating the coupled transfer of protons and electrons. This dissertation focuses on the physical chemistry aspects governing the properties of hydrogen bonds in several systems at the molecular level. The strength and dynamics of hydrogen bonded networks have important ramifications in protein structure and ligand docking. However, they are difficult to quantify in complex systems. There is an obvious energetic–structural–spectral correspondence for hydrogen bonds, relating their strength to the underlying structure of the participating covalent bonds and the ensuing infrared vibrational signatures. A physical model was developed that includes components describing the covalent DH bond of the hydrogen bond donor via a Morse potential, the Pauli repulsion, and electrostatic interactions between the constituent fragments. The model was fit to the ab initio potential energy surfaces of six archetypal hydrogen bonded dimers, namely NH3−NH3, H2O−H2O, HF−HF, H2O−NH3, HF−H2O, and HF−NH3. By applying this model, a simple linear relationship was derived for weak hydrogen bonds, viz. 8.0 kcal/mol per pm of the DH bond elongation (D refers to the hydrogen bond donor) or 4.5 kcal/mol per 100 cm−1 of the DH vibrational shift. In stronger hydrogen bonds, non-linear effects arise from a gradual onset of repulsion. The model accurately predicts the hydrogen bond energies in dimers and gas phase peptides from experimentally measured red-shifts in vibrational frequencies. This relationship provided a quantitative metric for previously undetermined hydrogen bond strengths and explained the fundamental causes for red-shifts in hydrogen bond frequencies. Hydrogen bonding interactions play a crucial role in describing the hydration and protonation sites of nicotine (NIC). Gas phase protonated NIC (NIC-H+) can exist as two isomers that are protonated in two different sites, viz. the pyrrolidine protomer (Pyrro-H+), which is bio-active through interactions with nicotinic acetylcholine receptors (nAChRs), and the bio-inactive pyridine protomer (Pyri-H+). A joint experimental-theoretical approach determined that gas-phase NIC-H+ is a mixture of the two protomers in a 6:4 (Pyri-H+:Pyrro-H+) ratio, whereas other less addictive NIC-like molecules (nicotinoids) largely biased the Pyri-H+ protomer. The hydration of NIC-H+ favored the Pyrro-H+ protomer due to the formation of hydrogen bonded bridges between the water molecules from the one protonation site to the other. These “water bridges” provide the framework for proton transfer between the two acidic sites via the Grotthuss mechanism. Ab initio calculations of the transition states and the intrinsic reaction paths connecting the various minima explain the appearance/disappearance of peaks in the infrared (IR) spectra associated with NIC’s two protonation sites upon increasing the number of water molecules solvating NIC-H+. The calculations revealed that the proton shuffles between the two protonation sites in the presence of 4 or more water molecules via the Grotthuss mechanism at the experimental temperatures (T =130 K). This mechanism is preferred over the bi-molecular vehicle mechanism, which may become possible at room temperature (T =300 K). The solvation of the intermediate hydronium-like structures proved to be critical in lowering the reaction barriers associated with the Grotthuss mechanism and thus facilitating the proton transfer. Electronic structure calculations and a many-body decomposition of the interaction of NIC-H+ with model binding pockets of the nAChR in the human brain suggested that the strength of interaction with these model pockets strongly correlates with the addictive character of NIC-like molecules. The difference in the binding strength were correlated to the gas phase energy difference between Pyri-H+ and Pyrro-H+, providing a simple molecular descriptor for the addictive character of NIC-like molecules. The network of hydrogen bonds has a significant impact on the structure and energetics of aqueous systems. We have established a set of descriptors to quantify the aggregation of water in the gas and the condensed phases at the molecular level. Structural descriptors such as the hydrogen bonded O-O distance (rOO), O-H-O angle (θOHO), O-O-O angle (θOOO), and the modified tetrahedral order parameter (qm, m= 2, 3, 4, 5) describe important structural changes upon aggregation. Descriptors such as the adjacency environment, hydrogen bond saturation (% HB), and number of non-short-circuited cycles describe the cooperative nature of hydrogen bonded networks. Using a previously developed database of 162,892 water cluster minima for (H2O)n, n=3–25, we found that rOO, θOHO, and qm correlated strongly with cluster stability. Changes in the adjacencies and cycle count provided insight into changes in the hydrogen bond network upon aggregation. This analysis has been expanded to the networks of liquid water obtained from molecular dynamic simulations at seven temperatures ranging from near the melting point (T =280 K) to near the boiling point (T =360 K). We find that changes to the adjacency environment, stemming from changes in the number of hydrogen bonds, perturb the water network and result in contracting the second solvation shell as temperature increases from 280 K to 330 K. The above findings all together serve to describe the structural, kinetic, and spectral properties of hydrogen bonded systems in the gas and the condensed phases.