Noncovalent
Interactions
Discover the weak but essential forces that shape protein folding, DNA base-pairing, and every living system: hydrogen bonds, ionic interactions, van der Waals forces, and the hydrophobic effect.
Biochemistry
What Are Noncovalent Interactions?
Noncovalent interactions are attractive or repulsive forces between molecules (or within a molecule) that do not involve sharing electron pairs. Unlike covalent bonds, they are individually weak: typically \( 4 \text{–} 30 \; \text{kJ/mol} \) compared to \( \sim 350 \; \text{kJ/mol} \) for a C–C covalent bond.
The Four Major Types
Hydrogen Bonds
Donor (N–H, O–H) shares H with an electronegative acceptor (O, N). Strength: \( \sim 12\text{–}30 \; \text{kJ/mol} \).
Ionic Interactions
Electrostatic attraction between full positive and negative charges (e.g., \(\text{NH}_3^+\) and \(\text{COO}^-\)). Strength: \( \sim 20 \; \text{kJ/mol} \) in water.
van der Waals
Transient dipole attractions between all atoms at close contact. Individually very weak: \( \sim 2\text{–}4 \; \text{kJ/mol} \).
Hydrophobic Effect
Nonpolar groups are driven together in water: not a true "force" but an entropy-driven phenomenon.
Weak Alone, Powerful Together
Hydrogen Bonds: The Workhorses
1
Donor: An electronegative atom (O, N) bonded to H pulls electron density away, leaving H with \( \delta^+ \).
2
Acceptor: A lone pair on another electronegative atom (O, N) is attracted to the \( \delta^+ \) hydrogen.
3
Geometry: Strongest when donor, H, and acceptor are nearly linear (\( \sim 180^\circ \)).
Ionic (Electrostatic) Interactions
Governed by Coulomb's law: \( F = \dfrac{k \, q_1 \, q_2}{\varepsilon \, r^2} \). In water (\( \varepsilon \approx 80 \)), the force is greatly reduced compared to vacuum. Ionic interactions in proteins are called salt bridges when they also include a hydrogen bond.
van der Waals Forces
London Dispersion
Transient, instantaneous dipoles induce dipoles in neighbors. Present in all atoms and molecules.
Optimal Distance
Attractive at moderate distance; strongly repulsive when electron clouds overlap: defines van der Waals radius.
The Hydrophobic Effect
Energy and Distance Dependence
| Interaction | Potential Energy vs. Distance (r) | Strength in Water | Range |
|---|---|---|---|
| Ionic | \( 1/r \) | \( \sim 20 \) kJ/mol | Long |
| H-bond | \( 1/r^3 \) | \( 12\text{–}30 \) kJ/mol | Medium |
| van der Waals | \( 1/r^6 \) | \( 2\text{–}4 \) kJ/mol | Very short |
| Hydrophobic | Not distance-based | Context-dependent | N/A |
H-Bond vs Ionic: Key Differences
Hydrogen Bond
Involves a partial charge (\( \delta^+ \)) on H.
Requires specific geometry (\( \sim 180^\circ \)).
Donor must have O–H or N–H.
Directional.
Requires specific geometry (\( \sim 180^\circ \)).
Donor must have O–H or N–H.
Directional.
Ionic (Salt Bridge)
Involves full formal charges.
Non-directional (spherically symmetric).
Strongly weakened by water (\( \varepsilon \approx 80 \)).
Omnidirectional.
Non-directional (spherically symmetric).
Strongly weakened by water (\( \varepsilon \approx 80 \)).
Omnidirectional.
How to Identify the Interaction
1
Check for full charges. Are there formal + and - charges? If yes: ionic interaction.
2
Look for O–H or N–H near O or N. Partial positive H pointing at a lone pair? That is a hydrogen bond.
3
Are both groups nonpolar? Hydrocarbons, aromatic rings, or aliphatic chains clustering in water: hydrophobic effect.
4
Close contact between any atoms? Even nonpolar atoms attract at short range via transient dipoles: van der Waals.
5
Multiple types can coexist. A salt bridge may include ionic + H-bond. Protein cores use hydrophobic + vdW together.
Example 1: DNA Base Pairing
Example 2: Protein Folding
Hydrophobic Core
Nonpolar side chains pack tightly, excluding water. This is the dominant driving force of folding.
Surface H-bonds
Backbone and polar side chains form H-bonds with water and each other at the protein surface.
Salt Bridges
Charged residues (Lys, Arg, Asp, Glu) form ionic + H-bond pairs that fine-tune stability.
Example 3: Membrane Self-Assembly
Common Mistakes
✕ "Hydrophobic bonds"
The hydrophobic effect is not a bond. It is an entropy-driven phenomenon caused by the release of ordered water, not a direct attraction between nonpolar molecules.
✕ H-bonds are covalent
Despite the name, hydrogen bonds are electrostatic (dipole-dipole), not electron-sharing covalent bonds. They are ~10-20 times weaker.
✕ Only polar molecules have vdW
London dispersion forces act on all atoms and molecules, including noble gases and completely nonpolar hydrocarbons.
Summary Comparison
| Property | H-bond | Ionic | vdW | Hydrophobic |
|---|---|---|---|---|
| Origin | Dipole-dipole | Charge-charge | Transient dipoles | Entropy of water |
| Strength | \(12\text{–}30\) kJ/mol | \(\sim 20\) kJ/mol | \(2\text{–}4\) kJ/mol | Variable |
| Directionality | Yes (linear) | No | No | No |
| Requires Water? | No | Weakened by water | No | Yes |
| Key Example | DNA base pairs | Salt bridges | Protein core packing | Membrane formation |
Question 1 of 5
Which noncovalent interaction is the primary driving force behind protein folding in aqueous solution?
The hydrophobic effect is the dominant driving force: burying nonpolar side chains away from water releases ordered water molecules, producing a large favorable entropy change that drives the protein to fold.
Question 2 of 5
A G–C base pair in DNA is held together by three hydrogen bonds, while an A–T pair has two. Which prediction follows?
More hydrogen bonds per base pair means more energy required to separate the strands. G–C pairs (3 H-bonds) are stronger than A–T pairs (2 H-bonds), so higher G–C content raises \( T_m \).
Question 3 of 5
Van der Waals (London dispersion) forces between two atoms depend on distance as:
The attractive component of the van der Waals (London dispersion) potential falls off as \( 1/r^6 \), which is why these forces are extremely short-range: they become negligible beyond a few angstroms.
Question 4 of 5
A salt bridge between Lys and Asp in a protein is much weaker in water than in vacuum. What primarily explains this?
Coulomb's law includes the dielectric constant \( \varepsilon \) in the denominator: \( F = kq_1q_2 / (\varepsilon r^2) \). Water's high \( \varepsilon \approx 80 \) shields electrostatic interactions, reducing ionic attraction by roughly 80-fold compared to vacuum.
Question 5 of 5
Which statement about hydrogen bonds is correct?
Hydrogen bonds are directional: they are strongest when the donor atom, hydrogen, and acceptor atom are arranged in a nearly linear geometry (\( \sim 180^\circ \)). They do not involve electron sharing (that would be covalent), and they can form in non-aqueous environments too.