Biomolecular Structures: Protein Structure Levels

• Biomolecular structures refer to the three-dimensional arrangement of atoms in molecules such as proteins, nucleic acids, carbohydrates, and lipids

Importance of Biomolecular Structures

• Biomolecular structure determines the function of a biomolecule
• Understanding these structures helps elucidate biological processes at the molecular level
• Structural knowledge aids in drug design, protein engineering, and understanding disease mechanisms

Levels of Protein Structure

• Primary structure: the linear sequence of amino acids in a polypeptide chain
• Determined by covalent bonds linking amino acids
• Dictates all subsequent levels of protein organization
• Secondary structure: local folding patterns stabilized by hydrogen bonds between the peptide backbone's amino and carboxyl groups
• Common motifs include alpha-helices and beta-sheets
• Tertiary structure: the overall three-dimensional arrangement of a single polypeptide chain
• Stabilized by various interactions, including hydrophobic interactions, hydrogen bonds, disulfide bridges, and ionic bonds between amino acid side chains
• Quaternary structure: the arrangement of multiple polypeptide chains (subunits) in a multi-subunit protein
• Subunits are held together by non-covalent interactions and sometimes disulfide bonds

Techniques for Determining Protein Structure

• X-ray crystallography: involves crystallizing a protein and diffracting X-rays through the crystal
• Diffraction patterns are used to calculate the electron density map, from which the protein's structure can be determined
• Nuclear magnetic resonance (NMR) spectroscopy: uses magnetic fields and radio waves to determine the structure of proteins in solution
• Useful for studying protein dynamics and proteins that are difficult to crystallize
• Cryo-electron microscopy (cryo-EM): a technique where samples are rapidly frozen and imaged using an electron microscope
• Enables the determination of structures of large macromolecular complexes and membrane proteins

Structure and Function of Nucleic Acids (DNA and RNA)

• DNA primary structure: a sequence of nucleotides containing a deoxyribose sugar, a phosphate group, and one of four nitrogenous bases (adenine, guanine, cytosine, and thymine)
• DNA secondary structure: a double helix formed by two complementary strands held together by hydrogen bonds between nitrogenous bases (A-T and G-C)
• DNA tertiary structure: supercoiling and packaging of DNA within the cell, often involving proteins such as histones in eukaryotes
• RNA primary structure: a sequence of nucleotides containing a ribose sugar, a phosphate group, and one of four nitrogenous bases (adenine, guanine, cytosine, and uracil)
• RNA secondary structure: complex folding patterns, including stem-loops, hairpins, and internal loops
• RNA tertiary structure: the three-dimensional arrangement of RNA molecules, often stabilized by metal ions and RNA-binding proteins

Carbohydrate Structure

• Monosaccharides: simple sugars such as glucose, fructose, and galactose
• Disaccharides: composed of two monosaccharides linked by a glycosidic bond (e.g., sucrose, lactose)
• Polysaccharides: long chains of monosaccharides linked by glycosidic bonds
• Examples include starch, cellulose, and glycogen, serving as energy storage and structural components
• Carbohydrates can be linear or branched, influencing their properties and functions

Lipid Structure

• Fatty acids: long hydrocarbon chains with a carboxyl group at one end
• Saturated fatty acids: contain only single bonds
• Unsaturated fatty acids: contain one or more double bonds
• Triacylglycerols (triglycerides): composed of glycerol and three fatty acids, serving as energy storage molecules
• Phospholipids: composed of glycerol, two fatty acids, a phosphate group, and a polar head group, forming the structural basis of cell membranes
• Steroids: lipids characterized by a four-ring structure (e.g., cholesterol, hormones)

Forces Stabilizing Biomolecular Structures

• Covalent bonds: strong bonds formed by sharing electrons between atoms
• Primarily responsible for the primary structure of biomolecules
• Hydrogen bonds: weak bonds formed between a hydrogen atom and an electronegative atom (e.g., oxygen, nitrogen)
• Important in stabilizing secondary and tertiary structures of proteins and nucleic acids
• Ionic bonds: bonds formed between oppositely charged ions
• Contribute to protein and nucleic acid stability
• Van der Waals forces: weak, short-range attractive forces between atoms
• Hydrophobic interactions: the tendency of nonpolar molecules to cluster together in an aqueous environment
• Significant in protein folding and membrane formation

Protein Folding

• Protein folding is the process by which a polypeptide chain acquires its native three-dimensional structure
• Driven by the need to bury hydrophobic residues in the protein interior and expose hydrophilic residues to the aqueous environment
• Molecular chaperones assist protein folding by preventing aggregation and misfolding
• Misfolded proteins can lead to non-functional proteins or form aggregates, causing diseases

Structural Motifs and Domains

• Structural motifs: recurring combinations of secondary structure elements that exhibit a specific three-dimensional arrangement
• Examples include helix-turn-helix, zinc fingers, and leucine zippers
• Domains: independently folding units within a protein that have a specific function
• Proteins may consist of one or more domains

Dynamics of Biomolecular Structures

• Biomolecular structures are not static; they exhibit flexibility and conformational changes
• Conformational changes are often essential for biological activity, such as enzyme catalysis and signal transduction
• Techniques such as NMR and molecular dynamics simulations are used to study biomolecular dynamics

Protein-Ligand Interactions

• Ligands are molecules that bind to proteins, influencing their function
• Binding is typically specific and depends on the shape and chemical properties of the ligand and the protein's binding site
• Examples include enzyme-substrate interactions, antibody-antigen interactions, and drug-target interactions
• Binding affinity is a measure of the strength of the interaction between a protein and its ligand

Structure-Based Drug Design

• Knowing the structure of a target protein enables the design of drugs that specifically bind to it
• Computational methods are used to screen potential drug candidates and optimize their binding affinity and selectivity
• Structural information aids in understanding drug resistance mechanisms and developing new therapeutic agents

Common Biomolecular Structure Databases

• Protein Data Bank (PDB): a repository for the three-dimensional structural data of large biological molecules, such as proteins and nucleic acids
• Cambridge Structural Database (CSD): a database for small-molecule crystal structures
• Nucleic Acid Database (NDB): a database containing information about nucleic acid structures