Biophysics - Week Three - Interactions Between Molecules in Living States PDF

Interactions between Molecules in Living States Biophysics Topics to be discussed Covalent and Noncovalent Bonds Chemical Equilibrium Energetics Objectives Review the important chemical and biochemical that comprise the cellular processes at the molecular level....

Interactions between Molecules in Living States Biophysics Topics to be discussed Covalent and Noncovalent Bonds Chemical Equilibrium Energetics Objectives Review the important chemical and biochemical that comprise the cellular processes at the molecular level. Covalent Bonding https://www.expii.com/t/covalent-bonding-biology-definition-role-10346  Strongest type of bond: Formed by the sharing of electrons between atoms. Essential for molecular structure: Covalent bonds Covalent bonds define the primary structure of biomolecules like proteins and nucleic acids. Examples in biomolecules: Phosphodiester bonds Peptide bonds between Glycosidic bonds between between nucleotides in DNA amino acids in proteins sugars in carbohydrates and RNA Covalent Bonding https://lh3.googleusercontent.com/proxy/VT0uEewfDQoel6DL3kkfXqw6Kf9TZqQZdA3WjWG- g6ptd9_7grJEL0Q1UmtQQWSNG2o4m78fNGDSI6F3ANFMwJHZBbnPTXoOR9n380ZorJhXkBs  https://courses.lumenlearning.com/suny-potsdam- organicchemistry/chapter/2-2-hybrid-orbitals/ Carbon Bonding Orbitals  Chiral vs achiral molecules https://socratic.org/organic-chemistry-1/r-and-s-configurations/chiral-and-achiral-molecules-1 Properties of water Polar solvent Allows the dissolving of polar and ionic substances Due to the differences in the electronegativities of hydrogen and oxygen atoms, giving water a polar nature with partial negative and positive charges. 2 unshared pairs of electrons allow water to interact with polar and ionic solutes, making it easy for these solutes to dissolve in water. Dipole of water http://ch301.cm.utexas.edu/imfs/#vsepr/shape-dipole.html  Plays an important role in the stabilization of proteins and nucleic acids Noncovalent Compared to covalent interactions, Interactions noncovalent interactions tend to be weaker. Stability of noncovalent bonds is only slightly above than the thermal energy present in normal biological systems Types of Noncovalent Interactions Hydrogen Bonds Ionic bonds Van der Waals Forces  Hydrogen bonds between amino acid side chains in proteins and between base pairs in DNA Examples of Ionic interactions between charged amino acid side noncovalent bonds chains in proteinsHydrophobic interactions in biomolecules between nonpolar amino acid side chains in proteins Van der Waals forces between all atoms in molecules Ionic Interactions Interactions that occur between cations and anions Strength depends on the distance of separation between the particles and the type of solvent (non- polar > polar) Bonds are non-directional https://en.wikibooks.org/wiki/Structural_Biochemistry/Chemic al_Bonding/Ionic_interaction  Ionic Interactions Ions get dissolved in water due to: Water surround ions with negative ends contact with cations and positive ends contact with anions. https://socratic.org/questions/52f1151702bf34733dc14e7e Hydrogen Bonds Formed by the interaction between the hydrogen atoms and the unshared electron pairs of highly electronegative atoms (like O and N) Directional in nature Requires alignment of the molecules for the hydrogen bond to form This directional nature allows for specificity to occur in certain molecules like DNA https://sciencenotes.org/hydrogen-bond-definition-and- examples/ Van der Waals Interaction Weakest of the non-covalent interactions Formed by the interaction between fluctuating induced dipoles in adjacent molecules Need to be adjacent to each other for the interaction to form. https://www.chemistrylearner.com/chemical-bonds/van-der- waals-forces  These are not considered actual bonds, but rather are considered as entropy-driven Hydrophobic aggregation Aims to reduce contact with water molecules in an environment interactions Importance: contributes to the formation of membranes, folding of proteins, and formation of double helical DNA https://www.nature.com/articles/517277a Molecular Complementarity Structurally complementary molecules bind oftentimes through noncovalent interactions. Complementarity affects the affinity (strength of interaction) and specificity (which molecules interact) Both are important for molecular function (proteins, nucleotides)  Protein structure and function: Noncovalent bonds are responsible for the unique three-dimensional structures of proteins, which determine their function. Enzyme catalysis: The formation and breaking of noncovalent Biophysical bonds during enzyme-substrate interactions facilitate chemical reactions. Implications of Noncovalent DNA structure and replication: Hydrogen bonds between base pairs in DNA are essential for its double-helical structure and Interactions accurate replication. Ligand-receptor interactions: Noncovalent bonds mediate the binding of ligands (e.g., hormones, drugs) to their specific receptors. Molecular self-assembly: Noncovalent interactions drive the spontaneous assembly of biological structures, such as membranes and organelles.  Quantifying Bond Strengths and Interactions 01 02 03 Thermodynamic Binding affinity: The Computational methods: parameters: The strength of strength of a ligand- Molecular dynamics noncovalent bonds can be receptor interaction is often simulations and other quantified using expressed as the computational techniques thermodynamic parameters dissociation constant (Kd), can be used to study the such as enthalpy (ΔH) and which is inversely related to dynamics and energetics of entropy (ΔS). binding affinity. molecular interactions. Case in point: Protein Folding  Protein folding is a complex process that Protein determines a protein's three-dimensional structure, which is essential for its function. Folding Both covalent and noncovalent bonds play crucial roles in this process. Covalent Bonds Peptide bonds: These covalent bonds link amino acids together to form a polypeptide chain, which is the primary structure of a protein. While peptide bonds are essential for the linear sequence of amino acids, they do not directly influence protein folding. Covalent Bonds Disulfide bonds: These covalent bonds form between cysteine residues in a protein, creating disulfide bridges that can stabilize the protein's tertiary structure. Disulfide bonds are often found in extracellular proteins where they contribute to stability in oxidizing environments. Noncovalent Bonds Hydrogen bonds: These weak interactions between hydrogen atoms and electronegative atoms (oxygen, nitrogen) are crucial for protein folding. Hydrogen bonds can form between amino acid side chains and between backbone atoms, contributing to secondary structure elements like α-helices and β- sheets. Noncovalent Bonds Hydrophobic interactions: Nonpolar amino acid side chains tend to cluster together in the interior of a protein to minimize their contact with water. This hydrophobic effect drives protein folding and contributes to the stability of the protein's tertiary structure. Noncovalent bonds Ionic interactions (salt bridges): Charged amino acid side chains can interact with each other through electrostatic attractions (salt bridges). These interactions can contribute to protein stability and specificity. Noncovalent bonds Van der Waals forces: These weak, short-range attractions between all atoms in a molecule play a role in protein folding by contributing to the packing of amino acid side chains. Folding Funnel The folding process can be visualized as a funnel- shaped energy landscape. The top of the funnel represents the unfolded state of the protein with many possible conformations. As the protein folds, it moves down the funnel toward the lowest energy state, which corresponds to the native structure. Noncovalent interactions drive the protein toward the native state, while covalent bonds provide a framework for the structure.  Amino acid sequence: The primary sequence of amino acids determines the potential for protein folding and the stability of the native structure. Factors that affect protein Chaperones: Proteins called chaperones can assist in protein folding by preventing misfolding folding and aggregation. Post-translational modifications: Modifications like phosphorylation or glycosylation can influence protein folding and stability. What if something goes wrong in the process of protein folding?  Protein misfolding can lead to a variety of diseases, collectively referred to as protein misfolding Implications diseases. of protein misfolding These diseases are characterized by the accumulation of misfolded proteins, often in the form of aggregates or amyloid fibrils.  Neurodegenerative Diseases Systemic Diseases Common Alzheimer's disease Type II diabetes protein Parkinson's disease Cystic fibrosis Huntington's disease Transthyretin misfolding Amyotrophic lateral amyloidosis sclerosis (ALS) diseases Prion diseases  Loss of function: Misfolded proteins may be unable to perform their normal functions, leading to disease. For example, in cystic fibrosis, mutations in the CFTR protein result in misfolding and a loss of chloride ion transport, causing severe lung disease. Mechanisms Gain of toxic function: Misfolded proteins can acquire new toxic properties, such as the ability to form aggregates that disrupt of protein cellular function. In Alzheimer's disease, amyloid-β protein aggregates form plaques in the brain, leading to neuronal death. misfolding Dominant negative effect: In some cases, misfolded proteins can interfere with the function of normal proteins, leading to disease. For example, in Huntington's disease, a mutant form of the huntingtin protein can form aggregates that interfere with the function of normal huntingtin, causing neurodegeneration.  A reaction is considered to be in equilibrium when the rate of Equilibrium forward and backward reactions are the same. Equation: Keq = kf/kr = [B]b/[A]a constants  Steady state concentrations and ratios are A big note different from the concentrations and ratios of a reaction in equilibrium Dissociation constants Measures the affinity of the interaction between DNA and proteins and between two proteins.  The pH of a solution is determined by the concentration of hydrogen pH of a ions. Formed from the solution dissociation of ions Neutral solutions, like pure water, have equal concentrations of hydrogen and hydroxyl ions. Acidic solutions have pH < 7.0 and basic solutions have pH > 7.0 Weak acids don’t dissociate fully Relationship between pH, pKa and acid dissociation At pH extremes, one or the other species makes up essentially 100% of the solution. At the pKa, a 50/50 ratio of the two forms is present. Titration In a titration, the conjugate acid form (HA) of a weak acid is stoichiometrically converted to its conjugate base form (A-) by the addition of a strong base. The ratios of [A-]/[HA] are indicated as a function of pH. https://s3-us-west-2.amazonaws.com/courses-images-archive-read-only/wp- content/uploads/sites/887/2015/05/23213917/CNX_Chem_14_07_titration2.jpg Triprotic weak acid It has 3 dissociable protons, 3 pKas, and 3 plateaus on its titration curve https://chem.libretexts.org/Courses/BethuneCookman_University/B-CU%3A_CH- 345_Quantitative_Analysis/CH345_Labs/Demonstrations_and_Techniques/General_Lab_Techniques/Tit ration/Titration_Of_A_Weak_Polyprotic_Acid  Enzyme Kinetics Biological Protein-Ligand Binding Relevance Thermodynamics  Km: The Michaelis constant, a measure of an enzyme's affinity for its substrate, is inversely related to the equilibrium constant for the enzyme-substrate complex formation. This implies that half of the sites of the enzymes are filled. Vmax: The maximum velocity of an enzyme-catalyzed reaction is influenced by the equilibrium constant for the product formation step. Michaelis-Menten Equation  Kd (Dissociation Constant): A lower Kd value Protein-ligand binding indicates a higher affinity of the ligand for the protein. Ka (Association Constant): The reciprocal of Kd, Ka represents the strength of the protein-ligand interaction. Equilibrium Constant Expression: The equilibrium constant for protein-ligand binding is given by the ratio of the dissociation rate constant (k-1) to the association rate constant (k1).  Gibbs Free Energy: The standard Gibbs free energy change (ΔG°) for protein-ligand binding is related to the equilibrium constant. A negative ΔG° indicates a spontaneous binding reaction. Thermodynamic Consideration Enthalpy and Entropy: The binding affinity is influenced by both enthalpic (energy changes due to bond formation) and entropic (changes in disorder) contributions. Free Energy of Reactions The free energy of a system or chemical compound is denoted by "G“ (units in Kcal/mole). Equation for Free Energy: ∆G = GProducts - GReactants Negative ∆G – the reaction moves towards the right side Zero ∆G – the reaction is at equilibrium Positive ∆G – the reaction goes to the left Gibbs free energy equation The ∆G for a reaction is determined by the enthalpy change (∆H) and entropy change (∆S) for the reaction. Equation: ∆G = ∆H - T ∆S ∆H reflects changes in the chemical bonds for all molecules in the reaction. ∆S reflects changes in the entropy (randomness) of all components participating in the reaction. Gibbs Free Energy Equation https://www.khanacademy.org/scie nce/biology/energy-and- enzymes/free-energy- tutorial/a/gibbs-free-energy How about calculating Gibbs Free Energy Equation inside the cells (concentration conditions)? ∆G = ∆G0' + 2.303 RT log Q Q = [products]/[reactants] (the mass action ratio) ∆G0’ = standard free energy change, where T = 298˚K, P = 1 atm, and the starting concentrations of all components (other than H+) is 1 M. Energy coupling Endergonic reactions of biochemistry very often are driven forward by coupling them to the hydrolysis of ATP. Important: ∆G1 + ∆G2 = ∆Gsum < 0  Assume that ∆G > 0 for reaction B + C  D. Very often ATP and Energy such a reaction can be driven forward via a high energy intermediate created via ATP phosphorylation. coupling B-p serves as a common intermediate in the two reactions which go forward because ∆Gsum < 0