Study Notes: Water and Non-Covalent Bonds – Molecular Foundation of Therapeutics

Objectives

• Define hydrogen bonding, hydrogen bond donors and hydrogen bond acceptors
• Define the terms: amphipathic, hydrophilic (lipophobic), hydrophobic (lipophilic) and hydrophobic effect
• List the factors that affect water solubility of biological molecules and describe how the properties of water affect the interactions among biomolecules
• Define covalent bonds, ionic bonds and Van der Waals bonds and describe how they occur
• Define the important parameters of thermodynamics (enthalpy, entropy and free Gibbs energy) describe How $\Delta G$ can be used to predict whether a reaction will occur spontaneously or not

Introduction to Biochemistry and Biomolecules

• What is biochemistry? The study of the molecular basis of life
• What are biomolecules?
  • A molecule is a collection of atoms held together by covalent bonds
  • Biomolecules may be small molecular weight compounds ($MW \lt 1000\ \mathrm{g/mol}$) or large macromolecules
  • The small molecules function as nutrients, cofactors, fuels, precursors to other molecules and building blocks of macromolecules
  • The macromolecules may have MW > 10^{10}\ \mathrm{g/mol}. They are polymers of smaller molecules

Important Classes of Biomolecules

• 1) Polysaccharides
  • Polymers of carbohydrates
  • Glycogen: polymer of glucose; storage form of glucose between meals
  • Starch and cellulose: polymers of glucose
  • Glycosaminoglycans (e.g., heparin): polymers of (modified) carbohydrates
• 2) Proteins
  • Polymers of amino acids
  • Roles: structural (bones, teeth, hair, skin, etc.), receptors in signaling pathways, enzymes that catalyze bond breakage and formation of biomolecules
• 3) Nucleic acids
  • Polymers of nucleotides
  • Derived from nucleus; DNA (deoxyribonucleic acid) and RNA (ribonucleic acid) function to convey genetic information
• 4) Phospholipids
  • Amphipathic molecules
  • Can self-associate to form lipid bilayers (major component of cell membranes)
  • Composition: hydrophobic portion (typically two long chain fatty acids, $16-22\ \mathrm{C}$) and a hydrophilic head group that contains negatively charged phosphate attached to a hydrophilic molecule such as choline or inositol

Water and Hydrogen Bonding

• Water is distributed between intracellular and extracellular compartments (interstitial fluids, blood, lymph)
• Water is a dipolar molecule with uneven electron distribution; forms hydrogen bonds with other polar molecules and acts as a solvent
• Terminology:
  • hydrophilic — water loving
  • lipophobic — lipid hating
  • lipophilic — lipid loving
  • hydrophobic — water hating

Hydrogen Bonding

• Occurs between an electron-rich atom with a lone pair (N, O) and an electron-deficient hydrogen

• The hydrogen is covalently bound to an electronegative atom (e.g., N or O)

• N has one lone pair and can accept one hydrogen bond; O has two lone pairs and can accept two hydrogen bonds

• Strength of a hydrogen bond can vary from weak to moderate in strength

• In hydrogen bonding, an interaction of orbitals takes place (a unique characteristic of hydrogen bonding)

• Hydrogen bond donor (HBD): the group in which (X–H) are bound covalently and X is the electronegative atom that has higher attraction for electrons; the bound H atom gains partial positive charge and can participate in the hydrogen bond

• Hydrogen bond acceptor (HBA): the functional group that provides an electron-rich atom to participate in the hydrogen bond

• Some functional groups can act as both hydrogen donor and hydrogen acceptor (e.g., OH or NH₂); at the binding site these groups can bind to one ligand as a hydrogen donor and to another as a hydrogen acceptor

Water Solubility and Hydrophobic/Hydrophilic Interactions

• Factors affecting water solubility:
  1) The ability to form hydrogen bonds
  2) Ionization of one or more of the functional groups
• If water is mixed with hydrophobic (lipophilic) molecules (e.g., oil):
  • Oils do not have ionic groups or dipoles to interact with water
  • They interact with each other instead of water
  • Water molecules are excluded from the oil layer because water wants to form hydrogen bonds but the hydrophobic molecules cannot
  • The separation of hydrophobic molecules from water is called the hydrophobic effect

Covalent, Ionic, and Van der Waals Bonds

• Covalent bonding: formed when two atoms with half-filled orbitals overlap and the electrons from these orbitals align with opposite spins, leading to energy stabilization

• Ionic (electrostatic/salt bridges) interactions: occur when two ions with opposite charges are attracted to form a bond

• Van der Waals interactions (London forces)

  • Very weak interactions that occur between hydrophobic regions of different molecules
  • Mechanism:
  • In neutral, non-polar regions, electron distribution is not perfectly even, creating temporary dipoles
  • The dipole in one molecule can induce a dipole in a neighboring molecule, leading to a weak attraction
  • Strength depends on the distance between molecules (binding proximity is critical)

• Example depiction (conceptual): drug binding to a target via hydrophobic regions, with transient dipoles and induced dipoles forming Van der Waals contacts

Thermodynamics vs Kinetics

• Thermodynamics: studies the spontaneity and direction/extent of a chemical reaction
• Kinetics: studies the speed of the reaction (how fast it occurs)

Thermodynamics in Biochemistry

• The free energy, G, is a thermodynamic variable that can be used to explain if a reaction will proceed to the right or left (as written)

• Relationship: $G = H - T S$

  • $H$ is the enthalpy (heat of the reaction)
  • $S$ is the entropy (randomness of the system)
  • $T$ is the temperature in Kelvin

• In a favorable reaction, heat will be released (products have lower energy) and the products will be more random (higher entropy)

• Reaction direction and spontaneity:

  • For a reaction written as A + B ⇌ C + D:
  • If \Delta G < 0, the reaction proceeds to the RIGHT (EXERGONIC)
  • If \Delta G > 0, the reaction proceeds to the LEFT (ENDERGONIC)
  • If $\Delta G = 0$, the system is at EQUILIBRIUM

• Practical implication: these principles help predict whether biological reactions (including drug-binding events) will occur spontaneously under given conditions

Self-Assessment Questions (Sample Questions from the Transcript)

1) The functional group that provides an electron-rich atom (e.g., O or N) to participate in the hydrogen bond is a) Hydrogen bond donor (HBD) b) Hydrogen bond acceptor (HBA)

2) Which of the following molecules is most likely to form a Hydrogen bond with water?

• a) Methane
• b) Ammonia

3) When adding Sodium Chloride (NaCl) to water, it dissolves readily. NaCl is:

• a) Hydrophilic
• b) Hydrophobic

4) When mixing avocado oil with water, oil separates and forms its own layer on top of the water layer. This phenomenon is known as:

• a) Hydrophilic effect
• b) Hydrophobic effect
• c) Amphipathic effect

5) Glycolysis (breaking down sugar molecules) in the body is an exergonic reaction that leads to the release of free energy. Based on the provided information, glycolysis occurs:

• a) Spontaneously
• b) Non-spontaneously

References (Selected)

• An Introduction to Medicinal Chemistry, Fifth Edition - Graham L. Patrick
• Chemistry: a molecular approach / Tro, Nivaldo J. (Fourth edition) (chapter 18)
• Sandmann B.J., & Newman A., & Knipp G.T. (2019). States of matter related to pharmaceutical formulations. Mobley W., Amiji M.M., & Cook T.J. (Eds.), Applied Physical Pharmacy, 3e. McGraw Hill
• Access to pharmacy resources: https://accesspharmacy-mhmedical-com.ezproxy.ttuhsc.edu/content.aspx?bookid=2619&sectionid=218642216