STRUCTURE & FUNCTION: Macromolecular structure determines function and regulation.

Core concepts of macromolecular structure and function


The learning goals below are categorized as introductory {A}, intermediate {B} and upper {C}.
 

1. Biological macromolecules are large and complex
Macromolecules are made up of basic molecular units. They include the proteins (polymers of amino acids), nucleic acids (polymers of nucleotides), carbohydrates (polymers of sugars) and lipids (with a variety of modular constituents). The biosynthesis and degradation of biological macromolecules involves linear polymerization, breakdown steps (proteins, nucleic acids and lipids) and may also involve branching/debranching (carbohydrates). These processes may involve multi-protein complexes (e.g. ribosome, proteasome) with complex regulation.

Associated learning goals
• Students should be able to discuss the diversity and complexity of various biologically relevant macromolecules and macromolecular assemblies in terms of evolutionary fitness. {A}
• Students should be able to describe the basic units of the macromolecules and the types of linkages between them
. {A}
• Students should be able to compare and contrast the processes involved in the biosynthesis of the major types of macromolecules (proteins, nucleic acids and carbohydrates
). {B}
• Students should be able to compare and contrast the processes involved in the degradation of the major types of macromolecules (proteins, nucleic acids and carbohydrates.{B}
• Students should understand that proteins are made up of domains and be able to discuss how the protein families arise from duplication of a primordial gene. {C}


 
2. Structure is determined by several factors
Covalent and non-covalent bonding govern the three dimensional structures of proteins and nucleic acids which impacts function. The amino acid sequences observed in nature are highly selected for biological function but do not necessarily adopt a unique folded structure. The structure (and hence function) of macromolecules is governed by foundational principles of chemistry such as: covalent bonds and polarity, bond rotations and vibrations, non-covalent interactions, the hydrophobic effect and dynamic aspects of molecular structure. The sequence (and hence structure and function) of proteins and nucleic acids can be altered by alternative splicing, mutation or chemical modification. Sequences (and hence structure and function) of macromolecules can evolve to create altered or new biological activities.

Associated learning goals
• Students should be able to recognize the repeating units in biological macromolecules and be able to discuss the structural impacts of the covalent and noncovalent interactions involved. {A}
• Students should be able to discuss the composition, evolutionary change and hence structural diversity of the various types of biological macromolecules found in organisms. {A}
• Students should be able to discuss the chemical and physical relationships between composition and structure of macromolecules
. {A}
• Students should be able to compare and contrast the primary, secondary, tertiary and quaternary structures of proteins and nucleic acids
. {B}
• Students should be able to use various bioinformatics approaches to analyze macromolecular primary sequence and structure
. {B}
• Students should be able to compare and contrast the effects of chemical modification of specific amino acids on a three dimensional structure of a protein
. {B}
• Students should be able to compare and contrast the ways in which a particular macromolecule might take on new functions through evolutionary changes. {B}
• Students should be able to use various bioinformatics and computational approaches to compare primary sequences and identify the impact of conservation and/or evolutionary change on the structure and function of macromolecules
. {C}
• Students should be able to predict the effects of mutations on the activity, structure or stability of a protein and design appropriate experiments to assess the effects of mutations
. {C}
• Students should be able to propose appropriate chemical or chemical biology approaches to explore the localization and interactions of biological macromolecules
. {C}
• Students should be able to discuss how mutations of a duplicated gene generate functional diversity. {C}
• Students should be able to evaluate chemical and energetic contributions to the appropriate levels of structure of the macromolecule and predict the effects of specific alterations of structure on the dynamic properties of the molecule
. {C}

 
3. Structure and function are related
Macromolecules interact with other molecules using a variety of non-covalent interactions. The specificity and affinity of these interactions are critical to biological function. Some macromolecules catalyze chemical reactions or facilitate physical processes (e.g. molecular transport), allowing them to proceed in ambient conditions. These processes can be quantitatively described by rate laws and thermodynamic principles, (e.g. collision theory, transition state theory, rate laws and equilibria, the effects of temperature and structure and chemical reactivity, Coulomb’s Law, Newton’s laws of motion, energy and stability, friction, diffusion, thermodynamics, and the concept of randomness and probability).

Associated learning goals

• Students should be able to use mechanistic reasoning to explain how an enzyme or ribozyme catalyzes a particular reaction. {A}
• Students should be able to discuss the basis for various types of enzyme mechanisms. {A}
• Students should be able to calculate enzymatic rates and compare these rates and relate these rates back to cellular or organismal homeostasis. {B}
• Students should be able to discuss various methods that can be used to determine affinity and stoichiometry of a ligand-macromolecule complex and relate the results to both thermodynamic and kinetic data. {B}
• Students should be able to critically assess contributions to specificity in a ligand-macromolecule complex and design experiments to both assess contributions to specificity and test hypotheses about ligand specificity in a complex. {C}
• Students should be able to predict the biological and chemical effects of either mutation or ligand structural change on the affinity of binding and design appropriate experiments to test their predictions. {C}


 
4. Macromolecular interactions
The interactions between macromolecules and other molecules rely on the same weak, noncovalent interactions that play the major role in stabilizing the three-dimensional structures of the macromolecules themselves. The hydrophobic effect, ionic interactions and hydrogen bonding interactions are prominent. The structural organization of interacting chemical groups in a binding site or an active site lends a high degree of specificity to these interactions. The specificity and affinity of these interactions are critical to biological function.

Associated learning goals
• Students should be able to discuss the impact of specificity or affinity changes on biological function and any potential evolutionary impact. {A}
• Students should be able to discuss the various methods that can be used to determine affinity and stoichiometry for a ligand-macromolecule complex and relate the results to both thermodynamic and kinetic data. {B}
• Students should be able to discuss the interactions between a variety of biological molecules (including proteins, nucleic acids, lipids, carbohydrates and small organics, etc.) and describe how these interactions impact specificity or affinity leading to changes in biological function. {B}
• Students should be able to predict the effects of either mutation or ligand structural change on the affinity of binding and design appropriate experiments to test their predictions
. {C}
• Students should be able to discuss the relationship between the temperature required for denaturation (Tm) and macromolecular structure. {C}


 
5. Macromolecular Structure is dynamic
Macromolecular structure is dynamic over a wide range of time scales, and the dynamic structural changes, large and small, are often critical for biological function. Small changes can come in the form of localized molecular vibrations that can facilitate the access of small molecules to interior portions of the macromolecule. Large conformational changes can come in the form of the motions of different macromolecular domains relative to each other to facilitate catalysis or other forms of work. Proteins can contain intrinsically unstructured domains. The lack of structure in solution may facilitate a function in which interactions must occur promiscuously with several other molecules. The dynamic structure of macromolecules enables rapid changes that impact the homeostasis of biochemical and molecular biological processes

Associated learning goals
• Students should be able discuss the time scales of various conformational effects in biological macromolecules {A} and design appropriate experiments to investigate ligand induced changes in conformation and dynamics. {C}
• Students should be able to discuss the structural basis for the dynamic properties of macromolecules and predict the effects of changes in dynamic properties {A} that
might result from alteration of primary sequence. {C}
• Students should be able to predict whether a sequence is ordered or disordered {C}
and discuss potential roles for disordered regions of proteins. {B}
• Students should be able to critically discuss the evidence for and against the roles of dynamics in macromolecular function
. {C}

 
6. The biological activity of macromolecules is often regulated
The biological activity of macromolecules is often regulated in one or more of a variety of hierarchical ways (e.g. inhibitors, activators, modifiers, synthesis, degradation and compartmentalization).

Associated learning goals
• Students should be able to compare and contrast various mechanisms for regulating the function of a macromolecule or an enzymatic reaction or pathway. {A}
• Students should be able to discuss the advantages and disadvantages of regulating a reaction allosterically
. {B}
• Students should be able to discuss examples of allosteric regulation, covalent regulation and gene level alterations of macromolecular structure-function
. {B}
• Students should be to use experimental data to assess the type of regulation in response to either homotropic or heterotropic ligands on a macromolecule. {C}
• Students should be able to design a model to explain the regulation of macromolecule structure-function. {C}
• Students should be able to describe how evolution has shaped the regulation of macromolecules and processes. {C}
• Students should be able to describe how changes in cellular homeostasis affect signaling and regulatory molecules and metabolic intermediates. {C}



7. The structure (and hence function) of macromolecules is governed by foundational principles of chemistry and physics

Associated learning goals
• Students should be able to relate basic principles of rate laws and equilibria to reactions and interactions and calculate appropriate thermodynamic parameters for reactions and interactions. {A}
• Students should be able to explain how a ligand, when introduced to a solution containing a macromolecule to which it can bind, interacts with the macromolecule
. {A}
• Students should be able to explain, using basic principles, the effects of temperature on an enzyme catalyzed reaction
. {B}
• Students should be able to discuss the dynamic properties of a macromolecule using foundational principles of physics
. {B}


8. A variety of experimental and computational approaches can be used to observe and quantitatively measure the structure, dynamics and function of biological macromolecules

Associated learning goals
• Students should be able to propose a purification scheme for a particular molecule in a mixture given the biophysical properties of the various molecules in the mix. {B}
• Students should be able to either propose experiments that would determine the quaternary structure of a molecule or be able to interpret data pertaining to tertiary and quaternary structure of molecules
. {B}
• Students should be able to explain how computational approaches can be used to explore protein-ligand interactions and discuss how the results of such computations can be explored experimentally
. {C}
• Students should be able to compare and contrast the computational approaches available to propose a three dimensional structure of a macromolecule and discuss how the proposed structure could be validated experimentally
. {C}