Peptides and Proteins: Structure and Function 2 MED103 PDF

Peptides and Proteins: Structure and Function 2 MED103 The Cell 2024-2025 Fall Assist. Prof. Dr. Onur BULUT Department of Medical Biochemistry School of Medicine Atılım University Learning Objectives Describe Secondary Structures of Proteins: Explain the characteristics of secondary structures,...

Peptides and Proteins: Structure and Function 2 MED103 The Cell 2024-2025 Fall Assist. Prof. Dr. Onur BULUT Department of Medical Biochemistry School of Medicine Atılım University Learning Objectives Describe Secondary Structures of Proteins: Explain the characteristics of secondary structures, including α-helices and β-sheets, and how hydrogen bonding stabilizes these formations. Understand Tertiary Structure: Describe the tertiary structure of proteins and identify the types of interactions that stabilize it. Explain Protein Denaturation: Define protein denaturation, list the factors that cause it, and discuss its effects on protein structure and function. Recognize Quaternary Structure: Describe the quaternary structure of proteins and the role of subunit interactions in complex proteins. Identify Stabilizing Interactions at Each Structural Level: Summarize the different types of interactions that stabilize each structural level (secondary, tertiary, and quaternary) and explain their importance in maintaining protein stability and function. OVERVIEW Amino Acids & Peptide Bonds: Proteins are composed of 20 amino acids linked by peptide bonds, forming a unique sequence that determines their 3D shape. Levels of Organization: Protein structure is analyzed in four levels: Primary: Linear amino acid sequence Secondary: Local folding patterns (e.g., α-helices, β-sheets) Tertiary: Overall 3D shape Quaternary: Multiple polypeptides interacting SECONDARY STRUCTURE OF PROTEINS The polypeptide backbone forms specific, regular arrangements of amino acids rather than a random structure. These arrangements, called secondary structures, include: α-helix β-sheet β-bend (β-turn) Commonly found in proteins and critical to their function. α-Helix Several different polypeptide helices are found in nature. Most common polypeptide helix: α-helix It is a spiral structure, consisting of: a tightly packed, coiled polypeptide backbone core the side chains of the component amino acids extending outward A very diverse group of proteins contains α- helices. Fibrous proteins (e.g., keratins in hair and skin) – rigidity influenced by disulfide bonds. Globular proteins (e.g., myoglobin) – flexible and α-Helix showing peptide highly α-helical. backbone Models of the α helix, showing different aspects of its structure. (a) Ball-and-stick model showing the intrachain hydrogen bonds. The repeat unit is a single turn of the helix, 3.6 residues. (b) The α helix viewed from one end, looking down the longitudinal axis. Note the positions of the R groups, represented by purple spheres. (c) As this space-filling model shows, the atoms in the center of the α helix are in very close contact. (d) Helical wheel projection of an α helix. This representation can be colored to identify surfaces with particular properties. The yellow residues, for example, could be hydrophobic and conform to an interface between the helix shown here and another part of the same or another polypeptide. The red (negative) and blue (positive) residues illustrate the potential for interaction of oppositely charged side chains separated by two residues in the helix. 1. Hydrogen bonding: Hydrogen bonding stabilizes the α-helix structure: Bonds form between the carbonyl oxygen of one peptide bond and the amide hydrogen of a bond four residues ahead. Bonds run parallel to the helix, linking nearly all peptide bonds. Collective strength: Many weak hydrogen bonds together stabilize the helix. 2. Amino acids per turn: Each turn of an α-helix contains 3.6 amino acids. Thus, amino acid residues spaced three or four residues apart in the primary sequence are spatially close together when folded in the α-helix. 3. Amino acids that disrupt an α-helix: Proline: Causes kinks due to incompatible geometry. Large number of charged amino acids (e.g., glutamate, lysine): Disrupt by forming ionic bonds or repelling each other. Amino acids with bulky side chains (e.g., tryptophan) or amino acids that branch at the β-carbon (e.g.,valine or isoleucine) can interfere with formation of the α-helix if abundant.  Permanent Waving Process: Involves reshaping hair by altering its molecular structure. Mechanism: Moist heat stretches hair's -keratin helices. Reducing Agent: Applied with heat to break disulfide bonds, uncoiling the helices. Oxidizing Agent: Reforms disulfide bonds in new positions, creating curls. Result: New shape is maintained due to cross-linkages, but growth of new hair returns to its natural form. β-Sheet Secondary structure where all components of the peptide bond participate in hydrogen bonding. Pleated appearance: Known as β-pleated sheets. Structure: Made of two or more extended peptide chains (β-strands), often shown as broad arrows. Hydrogen bonds are perpendicular to the backbone.  Arrangements: β-sheets can be antiparallel (alternating ends) or parallel (same ends aligned). Types of Hydrogen Bonds: Interchain bonds: Between separate chains. Intrachain bonds: Within a single chain folded back on itself. β-Bends (reverse turns, β-turns) Function: Reverse polypeptide direction, contributing to compact, globular shape. Location: Typically on protein surfaces, often with charged residues. Composition: Usually 4 amino acids, including proline (creates kinks) and glycine (small R-group). Stabilization: Hydrogen and ionic bonds. Nonrepetitive secondary structure: Repetitive structures: About 50% of globular proteins are α-helix or β-sheet. Nonrepetitive structures: The rest of the polypeptide chain forms loops or coils, which are less regular but not random. TERTIARY STRUCTURE OF GLOBULAR PROTEINS Determined by primary structure (amino acid sequence). Refers both to the folding of domains, and to the final arrangement of domains in the polypeptide. Domains: Basic units of structure and function. Globular protein structure: Compact, with close packing in the core. Insulin Hydrophobic side chains: Buried in the interior. Hydrophilic groups: Positioned on the surface. Classifying Proteins: four major types of protein groups based on polypeptide chains: 1. fibrous proteins = arranged in long strands or sheets (e.g., keratin and collagen) 2. globular proteins = folded into a spherical or globular shape (e.g., hemoglobin and immunoglobulins) 3. membrane proteins = embedded in hydrophobic lipid membranes (e.g., receptors and transporters) 4. intrinsically disordered proteins = lacking stable tertiary structures (e.g., transcription factors) Collagen Interactions stabilizing tertiary structure Amino acid sequence dictates the unique 3D structure of a polypeptide. Side chain interactions guide the folding into a compact structure. Four types of interactions stabilize the tertiary structure of globular proteins: 1. Disulfide bonds 2. Hydrophobic interactions 3. Hydrogen bonds 4. Ionic interactions 1. Disulfide bonds: Disulfide bonds are covalent links between two cysteine residues, forming a cystine. They can link cysteines separated by many amino acids or even on different polypeptide chains. The bond stabilizes the protein's 3D structure, protecting it from denaturation, especially in extracellular environments. Commonly found in secreted proteins, like immunoglobulins. 2. Hydrophobic interactions: Nonpolar side chains cluster in the interior of the polypeptide, interacting with other hydrophobic groups. Polar or charged side chains are typically on the surface, exposed to the polar solvent. This arrangement is energetically favorable and stabilizes the protein structure. 3. Hydrogen bonds: Side chains with oxygen- or nitrogen-bound hydrogen (e.g., serine, threonine) can form hydrogen bonds with electron-rich atoms. Hydrogen bonding with polar groups on the protein surface and the solvent increases protein solubility. 4. Ionic interactions: Negatively charged groups (e.g., carboxylate in aspartate or glutamate) can interact with positively charged groups (e.g., amino in lysine). These interactions contribute to protein stability and structure. Protein folding Role of Side Chains: Interactions among amino acid side chains determine the folding of linear polypeptide chains into functional 3D shapes. Folding Duration: Occurs within seconds to minutes in the cell through nonrandom, ordered pathways. Secondary Structure Formation: Driven by the hydrophobic effect, where hydrophobic groups aggregate as water is released. Combination of Structures: Small secondary structures combine to form larger structures. Tertiary Structure Stabilization: Additional events stabilize secondary structures, leading to tertiary structure formation. Final Form: Achieves a fully folded, native form characterized by a low-energy state. Denaturation of proteins Denaturation disrupts secondary and tertiary structures without breaking peptide bonds. Caused by heat, solvents, acids/bases, detergents, and heavy metals. Often irreversible; denatured proteins become insoluble and may precipitate. Reversible only under ideal conditions, allowing refolding to the native structure. QUATERNARY STRUCTURE OF PROTEINS Monomeric proteins have a single polypeptide chain, while others have multiple chains (subunits). Arrangement: The organization of these subunits is referred to as quaternary structure, held by noncovalent interactions. Functionality: Subunits may function independently or cooperatively. Example: In hemoglobin, oxygen binding to one subunit increases the affinity of the other subunits for oxygen. PROTEIN MISFOLDING Protein folding is complex and can lead to improperly folded molecules. Quality Control: Misfolded proteins are typically tagged for degradation within the cell. Limitations: The quality control system is not perfect, leading to potential accumulation of misfolded proteins. Aging Factor: Accumulation of aggregates is more common as individuals age. Disease Association: Deposits of misfolded proteins are linked to various diseases. Amyloid diseases: Amyloid Formation: Accumulation of insoluble aggregates called amyloids is linked to neurodegenerative disorders. Alzheimer's Disease (AD): Dominant component of amyloid plaques → amyloid β (Aβ), a neurotoxic peptide with 40– 42 amino acids. Aβ is derived from the amyloid precursor protein (APP) through enzymatic cleavages by secretases. Mechanism of Toxicity: Aβ aggregation leads to cognitive impairment characteristic of AD. Aβ peptides accumulate in brain parenchyma and around blood vessels. Familial vs. Sporadic Cases: Most AD cases are non- genetic; approximately 5% are familial.