Serotonin in the pocket: noncovalent interactions and neurotransmitter binding

Serotonin in the pocket:

noncovalent interactions and neurotransmitter binding

I. The Importance of Selective Binding
The recognition by a nerve cell that the neurotransmitter serotonin has appeared may, or may not, trigger a response by the nerve cell. Recognition of the serotonin molecule occurs when nerve cells have receptor molecules that selectively bind serotonin. By exploring how a serotonin receptor selectively recognizes serotonin, one will learn the general principles of selective binding that are found in many biochemical processes including enzyme-substrate binding, antigen-antibody binding, hormone-receptor binding and many, many more.
The introduction to selective binding will begin with a review of the different forces that may be used when molecules bind or stick together. It is important to note that a specific binding interaction may use one or more of the forces listed below. There is no requirement that every force be used in every binding interaction. For example, ionic bonds are not required to explain the relatively high boiling point of water. Likewise, some forces may used more than once with a given molecule. Using water again, each water molecule can participate in four different hydrogen bonds with neighboring water molecules.
After reviewing the forces in the pre-activity, the in-class exercise will examine the possible forces that might be used to “stick” a serotonin molecule to a nerve cell receptor. Later in the semester, the course will delve into how a protein molecule (e.g., a nerve cell receptor, an enzyme, an antibody, etc.) can create a specific binding site or binding pocket.

II. Binding Forces

A. Write a brief, one or two sentence, description of each binding force listed below.

1. London dispersion forces (a.k.a. van der Waals)_

Temporary fluctuations in electron density create momentary charge imbalances. These temporary charge imbalances create weak electrostatic attractions between areas of induced negative and positive charge. It is important to note that all molecules produce London dispersion forces.

2. Dipole-dipole forces

Polar bonds have permanent partial positive and negative charges. The electrostatic attraction between these partial charges provides the energy for the dipole-dipole attractive force.

3. Hydrogen bonding

Hydrogen bonding occurs when the hydrogen atom of a polar covalent bond (e.g., N—H or O—H bond) interacts with a lone pair of electrons on an electronegative element such as nitrogen, oxygen or sulfur.

4. Ionic interactions

Ionic interactions occur between oppositely charged ions with permanent formal charges of one or greater. Because these are ions are often loosely associated in solution, as opposed to packed in a crystal lattice, the strengths of these interactions are weaker than values reported from studies of crystalline compounds.

5. Hydrophobic interactions (note: Hydrophobic interactions appear where you might expect van der Waals interactions from organic chemistry. But, they are stronger and use a different mechanism.)

The hydrophobic effect occurs when non-polar regions of molecules associate with each other. It is usually argued that an increase in the disorder of solvent water provides entropic driving force that promotes the association. I include the hydrophobic effect in this lesson as beginning of conversation about this effect. This is important because the hydrophobic effect energy is substantially greater than the attractive energy provided by the London dispersion force.

6. Covalent bonds

Covalent bonds occur when there is a sharing of electrons between atoms. Typically, these atoms have similar electronegativities and the electron sharing is relatively equal.

B. Characteristics of Chemical Forces Responsible for Binding Interactions.

(Note: some of the values needed are from Table 1.3 in Garrett & Grisham/4e and the rest are available from other sources…)

Binding Force	Strength (kJ/mol)	Distance (nm)	Reference
Van der Waal’s (London)	0.40- 4.0	0.3 – 0.6	1
Hydrogen bonds	12 – 30	0.27 – 0.31	1
Ionic interactions	20	0.25	1
Hydrophobic effect	< 40	Not applicable	1
Covalent bonds (e.g., C-C, C-H)	C-C bond = 377 C-H bond = 423	C-C = 0.15 C-H = 0.11	2

References:

1. 
   Garrett RH, Grisham CM. 2013 Biochemistry, 5^th Edition. Brooks/Cole CENGAGE Learning. Belmont, CA.
   
2. 
   Bruice PY. 2014 Organic Chemistry, 7^th Edition. Pearson Education. Upper Saddle River, NJ.