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M1 - Biochemistry Protein Structure Dr. Grogan 1 NTPs amino acids Structure DNA RNA PROTEINS Function THE CENTRAL DOGMA 2 Proteins are the principal agents for expression of the information contained in the genome. 3 Proteins have wide ranging properties appropriate to their various functions. 4 5 Proteins may differ greatly in amino acid composition. 6 What can the amino acid composition of a protein tell you about its properties/function? For example: 1. A protein that is rich in hydrophobic amino acids 2. Histones – rich in Arg, Lys 7 Proteins often have constituents other than amino acids. 8 9 Proteins are constructed from various combinations of a relatively limited number of structural motifs. 10 The Four Levels of Protein Structure • Primary – the covalent bonded amino acid sequence • Secondary – non-covalent interactions between residues close to each other in the primary sequence • Tertiary – non-covalent or covalent interactions between secondary structural elements • Quaternary – non-covalent or covalent interactions between different polypeptide chains 11 The Four Levels of Protein Structure 12 Even the simplest proteins can assume many different conformations. BUT Only one or a few of these will be functional. 13 The Concept of Protein Folding How does a protein assume the conformation that will permit it to carry out its function? 14 Unfolded (denatured) Folded (native conformation) 15 General Principles Governing Protein Folding • Dictated by initial primary amino acid sequence • Sequential formation of higher order structures • Minimal energy structure 16 Characteristics of a Properly Folded (minimal energy) Protein • Hydrophobic residues in hydrophobic core • Most ionic and polar groups on surface • Polar groups that are inside interact with each other • No overlap in van der Waal’s radii. 17 Formation of Secondary Structure • The most stable and common forms are αhelix and β-sheet structures • Maximize hydrogen bonds between αaminos and α-carbonyls of peptide bonds • Maximize electrostatic interactions between R-groups • Minimize steric clashes between R-groups 18 How does amino acid sequence determine secondary structure? 19 Recall: Double bond character prevents rotation around the peptide bond. 20 The single bonds between the αcarbons and carbon and nitrogen of the peptide bond remain free to rotate. 21 However, steric hindrance limits that rotation to a certain range of angles φ and ψ. 22 Steric Hindrance Between an Amino Hydrogen and a Carbonyl Oxygen with Unfavorable Angles φ and ψ 23 β-sheet structures α-helical structures A Ramachandran plot showing angles φ and ψ that avoid steric clashes. 24 The α-helix maximizes the formation of Hbonds between the α-amino hydrogen and the carbonyl 4 residues removed in the primary sequence. 25 26 Arg Asp The stabilizing effect on the α-helix of electrostatic interaction between acidic and basic amino acids, 3 residues apart. 27 Conversely, bulky R-groups located in close proximity tend to destabilize an α-Helix 28 Charge distribution on the α-helix induces a partial positive charge at the amino terminus and a partial negative charge at the carboxyl terminus. 29 Effects of the Helical Dipole on Stability Acidic residues near the amino terminus stabilize. Basic residues near the amino terminus destabilize. Basic residues near the carboxyl terminus stabilize. Acidic residues near the carboxl terminus destabilize. 30 For reasons that we will discuss later, Gly and Pro residues also destabilize the α-helix. 31 β-Sheet: Another Type of Secondary Structure that Maximizes Hydrogen Bonding While Avoiding Steric Clashes 32 33 34 Loops and Turns Where the Polypeptide Chain Becomes More Disordered and Changes Direction 35 Gly and/or Pro residues disrupt helical or sheet structures and facilitate turns. • Gly contributes necessary flexibility because it lacks a bulky R-group. • Pro lacks the flexibility to accommodate helical or sheet structures but can form a cis peptide bond to effect a 180 degree turn. 36 37 38 For example, this sequence marks the carboxyl terminus of an αhelix found in a family of esterases: Ala-Arg-Asn-Gly-Ser-Pro 39