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Search Fundamentals of Biochemistry
Learning Goals (ChatGPT o1, 1/25/25)
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Understand the Mechanism of Peptide Bond Formation:
- Explain the process of dehydration synthesis that links amino acids, including the role of water loss in forming the amide (peptide) bond.
- Describe the chemical activation of the carboxylic acid group (via ATP and formation of a high-energy intermediate) that facilitates nucleophilic attack by the amino group.
- Recognize common misconceptions related to protonation states in peptide bond formation and clarify the proper chemical representation.
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Comprehend the Role of the Ribosome and Genetic Information:
- Describe how the ribosome, as a ribonucleoprotein nanoparticle, catalyzes peptide bond formation during translation.
- Connect the sequence information encoded in mRNA (and ultimately genomic DNA) to the primary sequence of a protein.
- Understand the directionality of protein synthesis (N-terminus to C-terminus) and its implications for protein structure.
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Define Protein Primary Structure:
- Identify the primary structure of a protein as its unique linear sequence of amino acids.
- Explain how the order of amino acids determines the eventual folding and function of the protein.
- Differentiate between peptides and proteins based on size, synthesis, and structural criteria.
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Explore the Diversity of Protein Sequences and Structures:
- Quantify the vast number of potential protein sequences even for short peptides and appreciate the diversity generated by 20 different amino acids.
- Discuss the hierarchical organization of protein structure (primary, secondary, tertiary, and quaternary) and the role of primary structure as the foundation for higher-order folding.
- Use examples (e.g., hydroxynitrile lyase) to illustrate how distinct regions of the primary sequence can adopt specific secondary structures (α-helices, β-sheets, coils) and contribute to overall tertiary and quaternary arrangements.
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Connect Chemical Structure to Protein Function:
- Analyze how the primary sequence and covalent peptide bonds establish the framework for protein folding and function.
- Discuss how post-translational modifications and disulfide bond formation (both intra- and inter-chain) further stabilize protein structure and mediate functional interactions.
- Relate the principles of peptide bond formation and sequence variability to the extraordinary range of protein functions in biological systems.
These learning goals will guide students in integrating chemical, structural, and genetic principles that underlie peptide synthesis and protein structure, setting the stage for deeper exploration of protein folding, function, and regulation in later chapters.
Peptide Bond Formation and Primary Protein Structure
Proteins are polymers of amino acids that fold into shapes that confer function on the proteins. In biological systems, the amino acids are linked by a large ribonucleic acid/protein nanoparticle called the ribosome. Thus, as the amino acids are linked together to form a specific protein, they are placed within a specific order dictated by the genetic information contained within a specific type of RNA called messenger RNA (mRNA). The mRNA sequences are encoded in the genomic DNA sequence. The specific ordering of amino acids is the protein's primary sequence. The translation mechanism used by the ribosome to synthesize proteins will be discussed in detail in Chapter 26.
The amino acids are linked together using dehydration synthesis (loss of water) reaction that connects the carboxylic acid of the upstream amino acid with the amine functional group of the downstream amino acid to form an amide linkage (Figure 2.10). You will remember from other chemistry courses that forming an amide from a carboxylic acid (thermodynamically stable)and an amine requires activating the carboxylic acid end to form a derivative with a better-leaving group. This carbonyl of the modified end serves as an electrophile in the attack of the amine nitrogen, a nucleophile, in a nucleophilic substitution reaction. The activation reaction, which we will discuss in subsequent chapters, involves the transfer of a phosphate from a phosphoanhydride, ATP, to the carboxylic acid group to form a mixed anhydride with the phosphate serving as a leaving group. Note that the reverse reaction is hydrolysis and requires the incorporation of a water molecule to separate two amino acids and break the amide bond. Notably, the ribosome serves as the enzyme that mediates the dehydration synthesis reactions required to build protein molecules, whereas a class of enzymes called proteases is required for protein hydrolysis.
A peptide bond is the amide linkage between amino acids in a protein. Subsequent amino acids will be added to the carboxylic acid terminal of the growing structure. Proteins are always synthesized directionally, starting with the amine and ending with the carboxylic acid tail. New amino acids are always added onto the carboxylic acid tail, never onto the amine of the first amino acid in the chain. The ribosome dictates the directionality of protein synthesis. Figure \(\PageIndex{1}\) below shows an overly simplistic version of the reaction that produces the amide bond.
Please note two features of the reaction as shown in the diagram:
- The activation step (phosphorylation of the carboxylic acid end of the amino acid by ATP) is not shown.
- The reaction is shown with an unlikely protonation state. If the carboxyl group is protonated, which would occur at a low pH, the amine would also be protonated and should correctly be shown as RNH3+. The protonation state in the above figure was chosen to emphasize the loss of H2O (dehydration) in the reaction. Many textbooks that aren't rigorously based in chemistry show unlikely protonation states for this reaction. By discussing this now, we hope to highlight common mistakes and misconceptions found in many resources.
Figure \(\PageIndex{2}\) shows a generic structure from a longer peptide or protein.
Proteins range in size from around 50 amino acids in length to rare proteins with molecular weights in the millions. One example is the human protein titin (alsocalled connectin), a muscle protein. The human version has over 34,000 amino acids and a molecular weight of over3.9 million! A polyketide synthase (PKSor a PKZILLAs) has 45,212 amino acids with amolecular weight of 4.7 million."Giant" proteins, up to 85,804amino acids, are encoded by some bacteria in the phylumOmnitrophotafound in wastewater and hot pools. However, only pieces of the protein are found.
Some consider structures with fewer than 50 amino acids as peptides (Figure 2.13). Others suggest that 40-50 amino acid structures should be considered small proteins. One way to differentiate them is by how they are synthesized in vivo. Storz et al consider polypeptides to be small proteins if they are encoded in the genome by a continuous stretch of DNA base in an "open reading frame" (doi: 10.1146/annurev-biochem-070611-102400). Peptides, on the other hand, could be structures that are:
- "intrinsically disordered" with no definite fold,
- derived from proteins by proteolysis and/or
- not synthesized by ribosomes
As genomes were sequences and annotated, some arbitrary parameters were set. For the yeast genome, annotated proteins were defined as those made from an open reading frame (ORF) in the DNA sequence that encodes the protein, leading to a polypeptide of 100 amino acids (which, on average, has a molecular weight of 11,000). If no cutoff were used, the number of proteins encoded by the genome would be huge. Submissions of DNA sequences to the NIH GenBank must encode proteins no smaller than about 66 amino acids (MW about 7250). Even this ignores small proteins that have been isolated and characterized from cells. So the cutoff of 50 amino acids (MW about 5500) derived from open reading frames seems like the best arbitrary cutoff in the transition frompeptides to proteins.
The definition of a protein as encoded in an "open reading frame" in the DNA/RNA is contingent on how you define an open reading frame. Evidence suggests that many proteins are made from atypical or noncanonicalopen reading frames (ncORFs). This study found that at least 25% of 7,264 ncORFs were transcribed and translated into over 3,000 peptides/proteins. Most DNA/RNA sequences were less than 100 codons (or the equivalent number of amino acids). Most were also within long noncoding RNAs (see RNA Chapter) or untranslated regions of messenger RNAs. Their functional significance is, in most cases, uncertain, yet their presence would expand the number of protein-encoding genes in the human genome.These sequences are available in two databases:GENCODE, which can identify and classify gene features in human and mouse genomes based on biological evidence, andPeptideAtlas, which houses peptide structures determined by mass spectroscopy. It's difficult to differentiate peptides transcribed from ncORFs from the 1000s of peptides produced in cells from proteolysis and other means. The new sequences, found in what has been called the "dark proteome," add 1000s of protein to the previous total of around 20,000 human protein-coding genes.
Due to the large pool of amino acids that can be incorporated at each position within the protein, billions of different possible protein combinations can be used to create novel protein structures! For example, think about a tripeptide made from this amino acid pool. At each position, 20 different options can be incorporated. Thus, the total number of resulting tripeptides possible would be 20 X 20 X 20 or 203, or 8,000 different tripeptide sequences! Now, think about how many options there would be for a small peptide containing 40 amino acids. There would be 2040 options or a mind-boggling 1.09 X 1052 potential sequence options! Each of these options would vary in the overall protein shape, as the nature of the amino acid side chains helps to determine the interaction of the protein with the other residues in the protein itself and with its surrounding environment.
Nearly 200,000 3D structures of biomacromolecules are known, and over a million have been determined using artificial intelligence computer programs. How can we simplify our understanding of the diversity of protein structures? Is each structure unique? What do they have in common?
To simplify and inform our understanding of the diversity of biological organisms, we place them into groups (from domains and kingdoms to genuses and species), based on common characteristics. Likewise, proteins are divided into a hierarchy of structures with increasing information content. This overview describes the four basic levels of protein structure: primary (10), secondary (20), tertiary (30), and quaternary (40).Each will be probed in greater detail in the next chapter. These classes of structures will be illustrated below with a protein named hydroxynitrile lyase (5Y02). (This protein has been simplified to illustrate key structural features, which will be described at the end.)
Primary (10) Structure: the amino acid sequence of a protein.
A protein's primary (10) structure is simply the amino acid sequence of a protein written from N- to C-terminal. It does not require visualization to describe it. Consider two different short continuous sequences from the hydroxynitrile lyase:
- Gln-Lys-Gln-Ile-Asp-Gln-Ile or in single letter code QKQIDQI. This is the sequence for amino acids 20-26 in the protein. This stretch of 10 structure has multiple repeated amino acids.
- Asp-Leu-Gly-Pro-Ala-Val or in single letter code DLGPAV. This is the sequence for amino acids 48-53 in the protein. This stretch of 10 structure does not contain repetitive amino acids.
A 2-D line drawing of the sequence offers more information but does not provide information about the conformation of these sections of 10 structures within a given protein. These can be shown in Figure \(\PageIndex{3}\), in which the protein's overall structure is shown in grey sticks with short stretches of primary structure shown in colored spacefill and 2D line drawings.
Figure \(\PageIndex{3}\): Alternative renderings of a "primary" sequence within a protein
Secondary (20) and Tertiary (30) Structures
Secondary (20) structures are repetitive structures within a protein held together by hydrogen bonds between amide Hs and carbonyl Os in the backbone main chain atoms. It's most easily examined through the specific rendering of the overall tertiary (30) or 3-D protein structure. Five different renderings showing the 3D (the tertiary) structure of the protein are shown in Figure \(\PageIndex{4}\).
Representation A shows a stick drawing of the protein with red indicating bonds to oxygen and blue bonds to nitrogen. No covalent bonds to hydrogen are shown as hydrogen atoms are too small to be detected using common techniques to determine the structures of such large molecules. It looks like a complicated mess of bonds, so understanding unique features with the 30 structure of the protein is difficult.Representation B shows just the backbone of the protein. The outline of how the protein twists and turns in space becomes more evident. The N- and C-terminal ends are more clearly seen.
Representation C shows just the bonds connecting the alpha C atoms of each amino acid. The protein's overall topology is now clearly evident. If you follow the chain from the N- to C-terminal ends, it should be evident that there are regularities in the conformations of the protein chain. The individual yellow zig-zags are called beta strands. These strands appear elongated and aligned with other beta strands to form a larger beta sheet. The sheet is held together through hydrogen bonds between backbone amide Hs and carbonyl Os on adjacent strands. Beta strands are a type of secondary structure.
The red zig-zag lines represent another type of secondary structure called the alpha helix. Hydrogen bonds hold the helix together between amide Hs and carbonyl Os within a single continuous strand. The backbone of the alpha helix appears less elongated than in a beta-strand as it is wound into a coil (the alpha helix) along a central axis. If you took tweezers (using atomic force microscopy) and pulled on the helix, it could stretch and become more elongated like the beta strands.
The remaining protein alpha carbon chain shown in blue is less regular. However, it is still ordered as it propagates through space in a random coil. It mainly adopts a fixed conformation but has more conformational flexibility than alpha helices and beta sheets. The alpha helices and beta strands (sheets) are examples of secondary structures.
Representations D and E are cartoon drawings clearly showing alpha helices (red), beta stands, and sheets (yellow). It would be extremely difficult to discern alpha or beta secondary structures with stick representations showing all the bonds in a protein. Some atoms must be removed visually (not literally) to see the protein backbone's repetitive propagation through the overall structure. A cartoon view alone would not be useful if you aimed to understand the disposition of side chains in a small part of a protein. Modeling programs allow mixed rending of a protein to include cartoon and stick representations.
Secondary structures, held together by hydrogen bonds between backbone atoms, are characterized by repetitive changes in thechain propagationanglebetween connected amino acids in an alpha helix and a beta-strand. In a given beta-strand, the relative change in the propagation angle is nearly 00 compared to a much larger angular change required to bend the amino acid backbone into an alpha helix. Here is the IUPAC definition of secondary structure. We added the word "repetitive" to show that random coils are not an example of secondary structures.
Definition: Secondary Structure (from the IUPAC Gold Book)
The [repetitive] conformational arrangement (α-helix, β-pleated sheet, etc.) of the backbone segments of a macromolecule, such as a polypeptide chain of a protein without regard to the conformation of the side chains or the relationship to other segments.
Quaternary Structure
Separate protein chains often interact through noncovalent interactions and sometimes through disulfide bond formation between free cysteine side chains on different chains to form dimers, trimers, tetramers, octamers, etc. Dimers can be homodimers (if the two chains are identical) or heterodimers (if they are different). The example in the section, hydroxynitrile lyase, forms a homodimer, as shown in Figure \(\PageIndex{5}\). The left image shows a cartoon version, with one monomer in orange and the other identical monomer in green. The right imageshows a translucent surface representation of the dimer, with the cartoon image underneath.
The mixed-rendered image on the right shows a translucent surface image of each monomer, and underneath the cartoon image
- primary structure: the linear amino acid sequence of a protein
- secondary structure: regular repeating structures arising when hydrogen bonds between the peptide backbone amide hydrogens and carbonyl oxygens occur at regular intervals within a given linear sequence (strand) of a protein or between two adjacent strands
Disulfide bonds within individual chains and between them stabilize both tertiary and quaternary structures of both peptides and proteins. These are illustrated in Figure \(\PageIndex{6}\).
Summary
Chapter Summary
This chapter delves into the foundation of protein structure by examining peptide bond formation and the concept of primary structure. It begins by outlining how proteins, as polymers of amino acids, are synthesized by the ribosome. This complex ribonucleoprotein machine translates the genetic code carried by mRNA into a specific linear sequence of amino acids. This sequence, known as the protein’s primary structure, is determined by the genomic DNA and dictates the protein's ultimate three-dimensional structure and function.
Key topics include:
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Peptide Bond Formation:
The chapter explains that amino acids are linked together via dehydration synthesis—a process that forms an amide (peptide) bond by losing water. It discusses the necessity of activating the carboxylic acid group (typically through phosphorylation using ATP) to create a better leaving group, thereby allowing the nucleophilic attack by the amine group of the incoming amino acid. The role of the ribosome in catalyzing this reaction and common misconceptions regarding protonation states during the reaction is clarified. -
Primary Protein Structure:
Emphasis is placed on the importance of the linear sequence of amino acids. The chapter details how the unique ordering of amino acids in a protein—ranging from short peptides to giant proteins like titin—forms the basis for its folding into higher-order structures (secondary, tertiary, and quaternary). This primary structure not only defines the chemical properties of the protein but also underlies its functional diversity in biological systems. -
Diversity and Definition of Proteins vs. Peptides:
The discussion highlights the enormous diversity possible from 20 amino acids and how even a short peptide can have millions of potential sequences. It also addresses the criteria used to distinguish between peptides and proteins, including size and the synthesis mechanism (continuous open reading frames versus proteolytic products). -
Hierarchy of Protein Structure:
Finally, the chapter introduces the concept of hierarchical protein organization—starting with the primary structure, moving through regular secondary structures (such as α-helices and β-sheets stabilized by hydrogen bonds), and culminating in complex tertiary and quaternary structures that often involve additional stabilizing elements like disulfide bonds.
Overall, this chapter lays the groundwork for understanding how the precise order of amino acids is essential for protein folding and function, setting the stage for more detailed studies of protein structure and dynamics in subsequent chapters.
References
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Fujiwara, K., Toda, H., and Ikeguchi, M. (2012) Dependence of a α-helical and β-sheet amino acid propensities on teh overall protein fold type. BMC Structural Biology 12:18. Available at: https://bmcstructbiol.biomedcentral.com/track/pdf/10.1186/1472-6807-12-18
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