The concept of stereochemistry, the spatial arrangement of the atoms within a molecule, is critical for understanding the structures and activities of biological molecules. As we shall see, the orientation of the chemical bonds of nucleic acids and proteins influences how these molecules fold in three dimensions, bind to other molecules, and catalyze reactions.

Our understanding of stereochemistry stems from a discovery by the French physicist Dominique Arago in 1811. Arago found that plane-polarized light, which vibrates in just one plane, rotates when it is sent through a piece of quartz crystal. Other scientists subsequently showed that many, but not all, substances share the ability to rotate the plane of plane-polarized light; a substance with this ability is said to be optically active. In 1848, 26-year-old chemist and crystallographer Louis Pasteur proposed that if a molecule is not superposable on its mirror image, it will be optically active; otherwise, it is optically inactive. This bold prediction subsequently proved to be correct. In fact, all objects can be classified as those that can be superposed on their mirror image, such as golf balls and champagne glasses, and those that cannot, such as hands. Objects that can be superposed on their mirror image are said to be achiral; those that cannot are chiral (Figure 3-22). All optically active chemical compounds are chiral, and all optically inactive compounds are achiral.

This is an important idea in molecular biology, because many biologically relevant molecules are chiral. For example, any carbon atom connected to four different groups—such as the α-carbon atom in an amino acid or certain carbons in the pentose sugars of nucleotides—is an asymmetric carbon atom, or chiral center. Thus, all nucleic acids and proteins are chiral, because they contain carbon atoms that are chiral centers, as we shall see shortly.

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Two molecules that have the same chemical and structural formula but differ in the arrangement of their atoms in space (i.e., are not superposable) are called stereoisomers. A pair of stereoisomers that are also mirror images of each other are called enantiomers. All physical and chemical properties of enantiomers are identical, except for two. First, the two enantiomers rotate the plane of plane-polarized light in opposite directions. Second, two enantiomers react at the same rate with any achiral compound but at different rates with any chiral compound.

For particular reference molecules selected by early chemists, including Pasteur, the one that rotates light to the right is called the (+) or d form (dextrorotatory), and the one that rotates light to the left is called the (−) or l form (levorotatory). Note that these “d” and “l” prefixes are distinct from the “D” and “L” prefixes (in small capitals) that refer to the actual configuration of each enantiomer (regardless of their light-rotating properties). Many chiral biological molecules are defined as D or L configurations based on their chemical relationship to the two forms of a reference compound, whether or not a pure solution of one form of that molecule is levorotatory or dextrorotatory. For amino acids, the reference compound is glyceraldehyde, and the version synthesized from (+) glyceraldehyde is considered to be the D form. Nine of the nineteen L-amino acids commonly found in proteins (glycine is achiral), however, are actually dextrorotatory!

Many biological molecules are chiral, and living organisms usually use only one of the two possible enantiomers. Thus, biochemical reactions have evolved to recognize and favor one stereoisomer over the other. For example, the simple sugar glucose is chiral. D-Glucose can be broken down by digestive enzymes, which are also chiral, at a rate commensurate with its use as an energy source. Because digestive enzymes are chiral, they do not recognize or digest glucose that has the opposite chirality (L-glucose), even though the two sugar molecules are identical in chemical and structural formulas.

Proteins are chiral because nearly all of the common amino acids contain an α carbon bonded to four different groups: a carboxyl group, an amino group, an R group, and a hydrogen atom. (The amino acid glycine is the exception, because its R group is simply a hydrogen atom.) The α carbon is therefore a chiral center, and the tetrahedral arrangement of the bonding orbitals around the α-carbon atom enables the four different functional groups to occupy two different possible spatial arrangements. This means that each amino acid, except glycine, has two possible stereoisomers. Because these are nonsuperposable mirror images of each other, the two forms are enantiomers (Figure 3-23a). Like all molecules with a chiral center, amino acids are optically active and rotate plane-polarized light. Nature uses only one of these enantiomeric forms in proteins, and it is the same one for each amino acid—the L form. D-Amino acids are almost never found in nature—a phenomenon that has been cleverly harnessed by researchers to design new therapeutics (Highlight 3-1).

Nucleic acids, too, are chiral molecules. Nucleotides contain several chiral centers in the ribose or deoxyribose ring—all of the carbon atoms in ribose except for C-5′ and all carbons in deoxyribose except for C-2′ or C-5′ are asymmetric (Figure 3-23b). Again, nature uses one enantiomeric form of the sugar—D-ribose or D-deoxyribose—in the building blocks for RNA and DNA. Enzymes that act on DNA or RNA have evolved to recognize this chiral arrangement of the nucleic acids.