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Aqueous Desolvation and Molecular Recognition: Experimental and Computational

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Aqueous Desolvation and Molecular Recognition: Experimental and Computational Aqueous Desolvation and Molecular Recognition: Experimental and Computational Studies of a Novel Host-Guest System Based on Cucurbit[7]uril by Yi Wang Department of Biochemistry Duke University Date:_______________________ Approved: ___________________________ Eric J. Toone, Co-Supervisor ___________________________ David N. Beratan, Co-Supervisor ___________________________ Terrence G. Oas ___________________________ Pei Zhou ___________________________ Patrick Charbonneau Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Biochemistry in the Graduate School of Duke University 2012 ABSTRACT Aqueous Desolvation and Molecular Recognition: Experimental and Computational Studies of a Novel Host-Guest System Based on Cucurbit[7]uril by Yi Wang Department of Biochemistry Duke University Date:_______________________ Approved: ___________________________ Eric J. Toone, Co-Supervisor ___________________________ David N. Beratan, Co-Supervisor ___________________________ Terrence G. Oas ___________________________ Pei Zhou ___________________________ Patrick Charbonneau An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Biochemistry in the Graduate School of Duke University 2012 Copyright by Yi Wang 2012 Abstract Molecular recognition is arguably the most elementary physical process essential for life that arises at the molecular scale. Molecular recognition drives events across virtually all length scales, from the folding of proteins and binding of ligands, to the organization of membranes and the function of muscles. Understanding such events at the molecular level is massively complicated by the unique medium in which life occurs: water. In contrast to recognition in non-aqueous solvents, which are driven largely by attractive interactions between binding partners, binding reactions in water are driven in large measure by the properties of the medium itself. Aqueous binding involves the loss of solute-solvent interactions (desolvation) and the concomitant formation of solute- solute interactions. Despite decades of research, aqueous binding remains poorly understood, a deficit that profoundly limits our ability to design effective pharmaceuticals and new enzymes. Particularly problematic is understanding the energetic consequences of aqueous desolvation, an area the Toone and Beratan groups have considered for many years. In this dissertation, we embark on a quest to shed new light on aqueous desolvation from two perspectives. In one component of this research, we improve current computational tools to study aqueous desolvation, employing quantum mechanics (QM), molecular dynamics (MD) and Monte Carlo (MC) simulations to better understand the behavior of water near molecular surfaces. In the other, we use a synthetic host, cucurbit[7]uril (CB[7]), in conjunction with a de novo series of ligands to study the iv structure and thermodynamics of aqueous desolvation in the context of ligand binding with atomic precision, a feat hitherto impossible. A simple and rigid macrocycle, CB[7] alleviates the drawbacks of protein systems for the study of aqueous ligand binding, that arise from conformational heterogeneity and prohibitive computational costs to model. We first constructed a novel host-guest system that facilitates internalization of the trimethylammonium (methonium) group from bulk water to the hydrophobic cavity of CB[7] with precise (atomic-scale) control over the position of the ligand with respect to the cavity. The process of internalization was investigated energetically using isothermal titration microcalorimetry and structurally by nuclear magnetic resonance (NMR) spectroscopy. We show that the transfer of methonium from bulk water to the CB[7] cavity is accompanied by an unfavorable desolvation enthalpy of just 0.49±0.27 kcal•mol-1, a value significantly less endothermic than those values suggested from previous gas-phase model studies. Our results offer a rationale for the wide distribution of methonium in biology and demonstrate important limitations to computational estimates of binding affinities based on simple solvent-accessible surface area approaches. To better understand our experimental results, we developed a two-dimensional lattice model of water based on random cluster structures that successfully reproduces the temperature-density anomaly of water with minimum computational cost. Using reported well-characterized ligands of CB[7], we probed water structure within the CB[7] cavity and identified an energetically perturbed cluster of water. We offer both experimental and v computational evidence that this unstable water cluster provides a significant portion of the driving force for encapsulation of hydrophobic guests. The studies reported herein shed important light on the thermodynamic and structural nature of aqueous desolvation, and bring our previous understanding of the hydrophobic effect based on ordered water and buried surface area into question. Our approach provides new tools to quantify the thermodynamics of functional group desolvation in the context of ligand binding, which will be of tremendous value for future research on ligand/drug design. vi Dedication This dissertation is dedicated to the teachers who inspired my enthusiasm towards science and technology (Mr. Lin Liang, Mr. Jing Sun, Mr. Xipeng Fang and Mr. Wenjun Qiao), to my mentors at University of Science and Technology of China and Duke University, to my family who have always believed in and supported me. vii Contents Abstract .............................................................................................................................. iv List of Tables ................................................................................................................... xvi List of Figures ................................................................................................................ xviii List of Schemes ............................................................................................................ xxviii List of Equations ............................................................................................................ xxix Acknowledgements ....................................................................................................... xxxv 1 Introduction ................................................................................................................... 1 1.1 General introduction ........................................................................................... 1 1.2 Intermolecular driving forces .............................................................................. 6 1.2.1 Electrostatic interactions ................................................................................. 7 1.2.2 van der Waals (vdW) interactions / Dispersion forces ................................. 10 1.2.3 The n-interactions .................................................................................... 13 1.2.3.1 Hydrogen bonds .................................................................................... 14 1.2.3.2 Halogen bonds ...................................................................................... 15 1.2.4 Interactions involving aromatic rings ........................................................... 17 1.3 Water as a solvent: a poorly understood critical player .................................... 19 1.3.1 The hydrophobic effect: a historical perspective .......................................... 22 1.3.1.1 Scaled particle theory ............................................................................ 33 1.3.1.2 Desolvation free energy ........................................................................ 39 1.3.2 Molecular structure of liquid water: an enduring mystery ............................ 44 1.3.2.1 The ongoing debate: tetrahedral or chain? ............................................ 44 viii 1.3.2.2 Cooperativity and anti-cooperativity of hydrogen bonding in water .... 50 1.3.3 Computer models of water ............................................................................ 54 1.3.3.1 Explicit models (one-site model) .......................................................... 55 1.3.3.2 Explicit model (three-site models) ........................................................ 60 1.3.3.3 Explicit model (four-site models) ......................................................... 62 1.3.3.4 Explicit model (five-site models) .......................................................... 63 1.3.3.5 Explicit models with non-pairwise additive interactions ...................... 65 1.3.3.6 Implicit models ..................................................................................... 66 1.4 Ligand binding in aqueous and non-aqueous solutions .................................... 68 1.4.1 Equilibrium binding constants and standard free energy .............................. 70 1.4.2 Definition of standard binding enthalpy and entropy ................................... 71 1.4.3 Definition of standard binding heat capacity ................................................ 74 1.4.4 Experimental approaches for determining binding thermodynamic parameters ................................................................................................................. 80 1.4.4.1 Light absorption techniques .................................................................
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