Protein Structures and Structure-Based Rational Drug Design
Proteins are macromolecules whose monomeric subunits are the naturally occurring 20 amino acids. The amino acids are linked via peptide bonds (generated upon water release) to form a polypeptide (► Chap. 1 ). Polypeptides can range in length from three t
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Protein Structures and Structure-Based Rational Drug Design 5.1 Protein Structure – 74 5.2 Signal Peptides – 74 5.3 Transmembrane Proteins – 77 5.4 Analyses of Protein Structures – 78 5.4.1 Protein Modeling – 78 5.4.2 Determination of Protein Structures by High-Throughput Methods – 78
5.5 Structure-Based Rational Drug Design – 79 5.5.1 A Docking Example Using DOCK – 80 5.5.2 Docking Example Using GOLD – 83 5.5.3 Pharmacophore Modeling and Searches – 84 5.5.4 Successes of Structure-Based Rational Drug Design – 85
5.6 Exercises – 86 References – 88
© Springer International Publishing AG, part of Springer Nature 2018 P.M. Selzer et al., Applied Bioinformatics, https://doi.org/10.1007/978-3-319-68301-0_5
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Chapter 5 · Protein Structures and Structure-Based Rational Drug Design
Protein Structure
Proteins are macromolecules whose monomeric subunits are the naturally occurring 20 amino acids. The amino acids are linked via peptide bonds (generated upon water release) to form a polypeptide (7 Chap. 1). Polypeptides can range in length from three to several hundred amino acids. The amino acid sequence of a given protein, also known as the primary structure, is genetically determined. It becomes fixed during translation based on the information encoded in the mRNA. The properties of an extended polypeptide chain correspond to a cross section of those of the corresponding amino acids, i.e., the function of the corresponding protein cannot be determined solely from the primary structure. It also depends on the spatial arrangement of the amino acids to one another. Stretched polypeptide chains fold spontaneously into secondary structures and then into three-dimensional (3D) structures. The secondary structure can comprise two main structural features, the α-helix and the β-sheet. These structural elements are connected via nonrepetitive elements called loops, which consist of irregular turns as third secondary structural elements. It is the combination of the positioning of the amino acid side chains and the peptide backbone of the secondary structure that forms the protein tertiary structure. If a protein consists of several subunits, then the association of these subunits to form the functional protein is called the quaternary structure. The function of a protein is mediated by its 3D structure, which, if known, can allow the inference of function. A reliable ab initio prediction of protein tertiary structure based solely on the primary structure is not yet possible, at least in the near future. Also, the experimental determination of structure is still difficult and the number of known protein structures comparatively small. Therefore, the prediction of the protein function based on the tertiary or quaternary structure is limited. However, proteins show a variety of structural and topological features that can be used to predict their properties and functions. Many of these features can be inferred or predicted from the primary structure by computational methods. Some of these properties and t
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