Chapter 33 — Further Reading

Textbooks

• Lehninger / Nelson and Cox. Principles of Biochemistry, 7th or later ed. (W. H. Freeman). Chapters 3-6 cover amino acids, peptides, protein structure, and enzyme catalysis. The standard biochemistry reference.

• Berg, J. M., et al. Biochemistry, 9th or later ed. (W. H. Freeman). Excellent treatment of protein structure and enzyme function.

• Voet, D., and Voet, J. G. Biochemistry, 4th ed. (Wiley, 2010). Comprehensive coverage.

• Fersht, A. (1999). Structure and Mechanism in Protein Science: A Guide to Enzyme Catalysis and Protein Folding. W. H. Freeman. The classic reference for enzyme mechanism and protein folding from a chemical perspective.

• Branden, C., and Tooze, J. (1998). Introduction to Protein Structure, 2nd ed. (Garland Science). Excellent introduction to protein structure with many beautiful illustrations.

• Walsh, C. T. (1979). Enzymatic Reaction Mechanisms. W. H. Freeman. Comprehensive treatment of enzyme catalysis chemistry; somewhat advanced but excellent.

• Petsko, G. A., and Ringe, D. (2004). Protein Structure and Function. Sinauer. Modern textbook with structural biology focus.

Primary literature: amino acid chemistry

• Sanger, F. (1955). The amino acid sequence of insulin. Nobel Lecture; British Medical Bulletin 11, 165–172. Sanger's classical paper sequencing the first protein.

• Anfinsen, C. B. (1973). "Principles that govern the folding of protein chains." Science 181(4096), 223–230. Anfinsen's Nobel lecture on protein folding (Nobel 1972).

• Pauling, L., and Corey, R. B. (1951). Series of papers on α-helix and β-sheet structure. Proceedings of the National Academy of Sciences USA 37(4-5), 205-285. Foundational papers on protein secondary structure.

• Kendrew, J. C., et al. (1958). The structure of myoglobin. Nature 181, 662. The first protein structure ever determined.

Primary literature: peptide synthesis

• Merrifield, R. B. (1963). "Solid phase peptide synthesis. I. The synthesis of a tetrapeptide." Journal of the American Chemical Society 85(14), 2149–2154. The original SPPS paper; Merrifield Nobel 1984.

• Carpino, L. A., and Han, G. Y. (1972). The 9-fluorenylmethyloxycarbonyl (Fmoc) amino-protecting group. Journal of Organic Chemistry 37(22), 3404–3409.

• Coin, I., et al. (2007). "Solid-phase peptide synthesis: from standard procedures to the synthesis of difficult sequences." Nature Protocols 2(12), 3247–3256. Modern review.

Primary literature: protein folding

• Levinthal, C. (1968). "Are there pathways for protein folding?" Journal of Chemical Physics 65, 44–45. The "Levinthal's paradox" paper.

• Bryngelson, J. D., et al. (1995). "Funnels, pathways, and the energy landscape of protein folding." Proteins: Structure, Function, and Bioinformatics 21(3), 167–195. The funneled energy landscape view.

• Wolynes, P. G. (multiple papers). The "principle of minimal frustration" and the energy landscape view of folding.

Primary literature: AlphaFold

• Jumper, J., et al. (2021). "Highly accurate protein structure prediction with AlphaFold." Nature 596, 583–589. The AlphaFold 2 paper.

• Tunyasuvunakool, K., et al. (2021). "Highly accurate protein structure prediction for the human proteome." Nature 596, 590–596. AlphaFold prediction of all human proteins.

• Varadi, M., et al. (2022). "AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space." Nucleic Acids Research 50(D1), D439–D444. The AlphaFold Database release.

• Abramson, J., et al. (2024). "Accurate structure prediction of biomolecular interactions with AlphaFold 3." Nature 630, 493–500. The AlphaFold 3 paper.

• Baek, M., et al. (2021). "Accurate prediction of protein structures and interactions using a three-track neural network." Science 373(6557), 871–876. RoseTTAFold (Baker lab).

Primary literature: enzyme catalysis

• Polgár, L. (2005). "The catalytic triad of serine peptidases." Cellular and Molecular Life Sciences 62(19-20), 2161–2172. Detailed review of serine protease catalysis.

• Carter, P., and Wells, J. A. (1988). "Dissecting the catalytic triad of a serine protease." Nature 332(6164), 564–568. Mutagenesis of subtilisin showing which residues matter.

• Wolfenden, R. (2011). "Benchmark reaction rates, the stability of biological molecules in water, and the evolution of catalytic power in enzymes." Annual Review of Biochemistry 80, 645–667. Quantitative measurements of enzyme rate enhancements.

Insulin and peptide drug history

• Banting, F. G., et al. (1922). "Pancreatic extracts in the treatment of diabetes mellitus." Canadian Medical Association Journal 12, 141–146. The original insulin discovery paper.

• Du Vigneaud, V. (1955). On the synthesis of oxytocin and the first peptide hormone synthesis. Du Vigneaud Nobel 1955.

• Itakura, K., et al. (1977). "Expression in Escherichia coli of a chemically synthesized gene for the hormone somatostatin." Science 198(4321), 1056–1063. Foundational paper on recombinant pharmaceutical production.

• Bell, J. R. (1988). "Insulin glargine and the new generation insulins." Reviews on engineered insulins.

Computational tools

• Avogadro (https://avogadro.cc/). Build amino acids; visualize α-helices and β-sheets.

• PyMOL (https://pymol.org/) or ChimeraX (https://www.cgl.ucsf.edu/chimerax/). Visualize protein structures from PDB or AlphaFold.

• AlphaFold Database (https://alphafold.ebi.ac.uk/). Free protein structure prediction database.

• PDB (https://www.rcsb.org/). Protein Data Bank; experimentally-determined structures.

• ColabFold (https://github.com/sokrypton/ColabFold). Run AlphaFold on Google Colab for any protein.

Online resources

• UniProt (https://www.uniprot.org/). The protein sequence and function database. Cross-referenced with AlphaFold.

• Pfam (https://www.ebi.ac.uk/interpro/). Protein family and domain database.

• ExPASy (https://www.expasy.org/). Many bioinformatics tools.

• Khan Academy: Biology — videos on amino acids and proteins.

For practice problems

• Klein, David. Organic Chemistry as a Second Language, 4th ed. (Wiley). Chapter on amino acids and proteins.

• Karty, Joel. Organic Chemistry: Principles and Mechanisms, 2nd ed. (W. W. Norton, 2018). Chapter on amino acids and proteins.

• Sorrell, Thomas N. Organic Chemistry, 2nd ed. (University Science Books, 2006). Chapter on amino acids and proteins.

Mathematically inclined readers

• Dill, K. A., and Chan, H. S. (1997). "From Levinthal to pathways to funnels." Nature Structural Biology 4, 10–19. Mathematical analysis of folding kinetics.

• Onuchic, J. N., et al. (1997). "Theory of protein folding: the energy landscape perspective." Annual Review of Physical Chemistry 48, 545–600. Statistical mechanics of folding.

Notes on this chapter's pedagogy

Chapter 33 is the central application of carbonyl chemistry to biological macromolecules. The unifying view: amino acids are α-amino carboxylic acids; peptide bonds are amides (Ch 26); protein folding is thermodynamic; enzyme catalysis uses side-chain chemistry. Each concept builds on Part VI.

The chapter ends with the AlphaFold revolution — a striking example of how computational chemistry + machine learning can solve a hard biological problem. This is forward-looking content; in 5-10 years, AlphaFold-style tools will be ubiquitous in biology.

Chapter 34 turns to the third great class of biomolecules: lipids and biosynthesis.