Lecture 1 - Introduction to Biological Macro Molecules

8/14/2019 Lecture 1 - Introduction to Biological Macro Molecules

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Biopolymer Sequence and

Structure

Instructor Contact Information:

John A. Rose, PhD (Assoc. Prof., APU ICTInstitute) APU Office: Building B, Room 414

Phone: x4414

E-mail:[email protected] Website: http://www.apu.ac.jp/~jarose/


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Text Material

Primary Text: Principles of Physical Biochemistry(Chapters 1-4)

K. E. van Holde, W. C. Johnson, and P. S. Ho

Prentice Hall, 1998; ISBN 0-13-720459-0

Supplementary Texts: Biophysical Chemistry, Parts I and III

C. R. Cantor and P. R. Schimmel

W. H. Freeman and Co., 1980; ISBN 0-71 7-1189-3.

Principles of Protein Structure

G. E. Schultz and R. H. Schirmer

Springer-Verlag, 1979; ISBN 0-387-90334-8.

Introduction to Computational Chemistry(Ch. 2 andCh. 16)

F. Jensen Wiley, 2001; ISBN 0-471-98425-6


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Introduction

Physical Biochemistry addresses the physical properties of

biological macromolecules:

1. Proteins (polypeptides).2. DNA, RNA (polynucleotides).

3. Sugars (polysaccharides).

Here, our main focus is on proteins and

polynucleotides. the information-carrying molecules of life.

However, the techniques we develop willalso apply to other biological

macromolecules.


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Our Focus PhysicalProperties

Physical Properties of biological macromolecules: provide a hierarchical description of molecular

structure: atomic level;

molecular level; level of large subunit assemblies.

measured by observing their interaction withelectromagnetic radiation: Ultraviolet (UV) spectroscopy.

X-ray crystallography. Nuclear Magnetic Resonance (NMR), etc.

An understanding of these properties facilitatesstructural prediction. Does information about molecule sequence tell us about

structure? If so, why??


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Secondary Focus

Biophysical Chemistry has 2 points of focus: Structural modeling and prediction; Structure determination:

experimental methods.

methods of interpreting experimental results.

In this course, we focus on structural prediction. Goal is to understand the essential physical aspects of

biomolecular structure: the role of symmetry;

the various stabilizing forces;

solvent contributions to structure;

statistical distributions over accessible states (structures).

Overall Course Goal: Acquire the background necessary for work in

Bioinformatics


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Relationship to Biochemistry

We note thatBiochemistry is also concerned with the structure of

biological macromolecules.

Focus: biologically important molecularmechanisms. e.g., specific details of active-site chemistry. often involves formation/breakage of covalent

bonds.

Biophysical Chemistry has a different focus: A quantitative analysis of structure, and The physical properties that determine the

range of structures which are accessible.

concerned primarily with changes in non-


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Our Primary ToolsThe first part of the course is mainly descriptive:

Focus: An overview of water and biopolymer structure.

In Part II, we also develop a tool for structuralprediction:

Statistical Thermodynamics uses experimentally determined free energies. estimates the probability of occupancy of various folded

structures, at equilibrium. also concerns changes in state variables which occur

upon a change of state. No description of rates, motion, or times to equilibrium.


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Course Organization(Tentative)

11 Basic Lectures (3 Units) + 1 ResearchLecture: Unit 1 Introduction to Biological Macromolecules

L1: Introduction and terminology;

L2-3: Structure of Water, Symmetry Concepts. L4-5: Protein Structure

L6: Nucleic Acid Structure

Unit 2 Thermodynamics for Biology

L7: Heat, Work, Energy, and the 1st Law ofThermodynamics.

L8: Entropy, Free energy, Equilibrium, and the 2nd Law.

Unit 3 Statistical Thermodynamics

L9: Introduction to Modeling. L10: Structural Transitions in Pol e tides/Proteins.


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Course Evaluation (Grading)

The final grade (100%) will be awarded usingthe following criteria for evaluation (tentative):

Attendance:20% Students should come to each class.

Note 1: students with more than 3 unexcused absenceswill receive an automatic F grade in thecourse.

Note 2: points will be deducted for lateness andbreaking lab rules.

Mid-term Exam: 35% An in-class test after Lecture 6 (tentative)

Final Examination: 45% A comprehensive, in class test over all course material.

Note: The above weights/items are subject to change.


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Lecture 1 Introduction toBiophysical Chemistry

Lecture 1 Outline: 1.1 Basic Terminology.

1.2 Review of Monomer Stereochemistry.

1.3 Weak Interactions in Macromolecular Structure.


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Definition of Molecule

Chemistry a molecule

contains 2 or more atoms; atoms covalently (tightly) bonded in specific proportions;

i.e., chemical formula (stoichiometry). also has a specific geometry.

Biochemistry takes a larger view a molecule:

also has well-defined stoichiometry and geometry; not readily dissociatedbut, bonds not necessarily

covalent. e.g.: Hemoglobin has 4 distinct polypeptide subunits:

each is a covalently-linked polymer chain. each chain is called a monomer.

monomers may be held together by non-covalentinteractions.


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Basic Definition: Structure

Stoichiometry often expressed by monomercomposition:

In any case, structure refers to the unique, linear


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The BiologicalMacromolecule

Simply puta macromolecule is a largemolecule. By large, we mean large enough to be conveniently

divided into distinct subunits. May be several levels of decomposition into

monomers.

For us, a macromolecule is typically abiopolymer: i.e., is composed of a string of monomer subunits.

Proteins: amino acid residues. RNA and DNA: nucleic acid residues. Polysaccharides: sugar residues.

This decomposition admits a useful notion of size:

oligomer: length 25 monomer subunits.


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The Hierarchical Structure ofBiopolymers

Monomers basic repetitive subunits.

Primary Structure (1o)

linear sequence of monomers

with a specific strand orientation.

Secondary Structure (2o)

the local, regular structure of biomolecules.

these are helical structures.

Tertiary Structure (3o

) global, 3-D fold or topology.

= native structure, for single-subunit biopolymers.

Quaternary Structure (4o)

spatial arrangement of multiple, covalently distinctsubunits.


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Illustrative Example

Hierarchical Structure ofHemoglobin:

Not all biopolymers have all 4 levels ofstructure. but, at least 2

ostructure required for function

Functionality usually requires a correlation: Between sequence and shape (Anfinsen).


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The Folding Problems ofBiophysical Chemistry

Function intimately related to Shape: e.g.: Lock and Key model of enzyme action.

A Primary Goal of Biophysical Chemistry: understanding the rules relating the 4 levels

prediction of 2o

and 3o

structure from 1o

structure. Best-known: the Protein Folding Problem;

currently unsolved. A Folding problem exists for each biopolymer class.

Before examining biopolymer structure, lets first review ome general principles

C fi ti


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Configuration vs.Conformation

The arrangement of atoms or groups in amolecule is described by two terms: Configuration refers to the arrangement around:

one or more non-rotating bonds, or

around a stereocenter (chiral center). Change of configuration requires a chemical change.

Breaking one or more covalent bonds.

Conformation arrangement about freely rotatingbonds.

change of conformation does not require a chemicalchange.

Both describe the spatial geometry ofbiopolymers.

However, they are very different terms.


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Configuration

Configuration refers to the position of atoms/groups: around one or more non-rotating bonds. Or, around a stereocenter.

Change of configuration requires a chemical change: breaking and remaking chemical bonds.

Example 1:Rotation about a double bond

requires breakage of a -bond with rotation through an sp

3intermediate.


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Configuration (cont.)

Example 2:Conversion b/w Enantiomers. i.e., molecules which are non-super-imposable mirror

images.

Conversion b/w L- and D-Glyceraldehyde

requires breakage of a single bond;

formation of a planar, achiral intermediate.


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Conformation

Conformation refers to the spatial arrangementabout freely rotating bonds. conformation can be changed by rotations about single

bonds;

does not require a chemical change. different conformations of the same molecule are called

structural isomers.

Example: Rotation about the central bond of 1,2-dicholoroethane.


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Monomer Stereochemistry

The monomer building-blocks ofbiopolymers are almost always chiralmolecules.

exhibit definite handedness. there are thus, two distinct forms

L-form - left-handed

D-form - right-handed.

these are mirror images, and are not super-imposable.

referred to as enantiomers.

Note: these are also called the S and R forms, aswell.

Enantiomers are distinct molecules.

E l L D


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Example: L vs. D-Glyceraldehyde

Each chiral center has 4 attached groups.

2. Assign grouppriorities:

a (highest) to d(lowest).

first basis: atomic massof directly connectedatom.

next basis: atomicmasses of next closestatoms, etc.

3. Rotate d into the

plane.


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Chirality and Biopolymers

Biopolymers are generally constructed ofonly one enantiomer Each type of monomer units either L- or D-form

Required for formation of regular helices;This facilitates a correlation between 1

oand 2

o

structure.

Amino acids in natural proteins are usually L-form.

Sugar moiety of the nucleotides which composeDNA (2-Deoxyribose) is D-form.

Handedness has biological implications: distinct handedness lends specificity to 3-point

contact.Handedness also has eometric


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Macromolecular Conformation

Macromolecule conformation described by: conformation of each freely rotating bond.

For a biopolymer, the set of accessible

conformations: the structural isomers generated by these rotations.

Traditionally, conformation about each singlebond: described in terms of a 4-atom center, A-B-C-D defined

by the rotating bond, where B-C is the rotating bond.

A and D are the bulky (non-hydrogen) groups of theconnected, tetrahedral centers.

Example: 1,2-Dichoroethane. 4 atom center: Cl-C-C-Cl.

The Torsion and Dihedral


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The Torsion and DihedralAngles

Conformation of a 4-atom centerconveniently described in termsof: the torsion angle, :

defined between planes ABC and

DCB relative to A (looking down BC).

= 0o

when A and D are in cis. (+) defined as CW rotation of D. Standard for polymer chemistry

An equivalent description is thedihedral angle, : In Geometry:

Angle b/w normals of planes ABC andBCD.

+ = 180o

(see figure)

Thus: and supplementary. In Polymer Chemistry (slightly


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Descriptive Notation

Conformation also traditionally described interms of: relative placement of the bulky groups, A and D. Syn/Anti:

bulkiest groups on the same/opposite side of aplane through central bond, B-C.

Eclipsed/Staggered: bonds A-B and C-D overlapping/non-overlapping.


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The Impact of ConformationalChanges

A conformational change in abiopolymer can result in large changesin physical properties. Example: Protein Denaturation

The properly folded conformation of aprotein is biologically active. the native state.

In contrast, the unfolded conformation is not biologically active. the denatured state.

Thus, Conformation and Configuration

Each has important implications forbio ol mer sha e and function


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Molecular Interactions inMacromolecular Structures

For a macromolecule in a cellular environment: configuration is fixed by covalent bonding.

conformations, however, are highly variable

The sequence-dependent folding of abiopolymer: is no more than a change in conformation.

is dependent on a number of interactions:

between the atoms within the biopolymer. between the biopolymer and its environment.

A detailed description of stabilizinginteractions will be presented later on... with implications for modeling biopolymers.

Here, we give a brief description

Covalent vs Weak


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Covalent vs. WeakInteractions

The configurations of biopolymers are fixed: because covalent bonds require much energy to break...

Interaction Energies 200 800 kJ/mol

in contrast, thermal energy: RT = 2.58 kJ/mol (37o

C). Note 1: 1 mole of a particular molecule = 6.023 x 1023 copies

Note 2: Joule = a unit of energy equal to 1 Newton-meter

at ambient temperatures, can be treated as invariant (fixed). In other words, our molecules do not shake apart at room temperature!

The conformations of biopolymers:

stabilized by weak interactions. 1-2 orders of magnitude smaller than covalent interactions. Only 1 order of magnitude (10x) greater than RT.

These interactions describe how the atoms or groups attract orrepel Together, determine the total energy of a given conformation. Rule: the lower the energythe more favorable the structure.


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The Weak Interactions

The conformations ofbiopolymers: determined by weak

interactions.

The Weak Interactions: also called non-bonding. much weaker than

covalent interactions. 1 to 10s of kJ/mol.

include: Electrostatic (charge-

charge). Dipole-dipole, charge-dipole.

van der Waals. H dro en bondin .


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Distance-dependence of theWeak Interactions

Are all pairwise, distance-dependentinteractions. Energy of each 1/r

m. ; m = 1, 2, 3, 6, 12 (integer).

r = separation between a pair of interacting atoms orgroups.

The range of the interaction determined by m. for larger m values, V falls to zero more rapidly, with

increasing r.

Longest range: Charge-Charge interaction (m = 1). Shortest range: Steric repulsion (m = 12).


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Dependence on the Medium

The energies of long-range interaction alldepend on the intervening medium. Coulombic, charge-dipole, dipole-dipole.

Example: Interaction b/w 2 charges becomes shielded in a

polar or polarizable medium.

Example: Water

dipoles of the medium line up to oppose the E-field. Result: Interaction is weakened.


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The Dielectric Constant

Long-range interactions all reduced by a factorof 1/. the dielectric constant. = /o = Eo/E

, = permittivity of our medium, and of freespace, respectively.

a measure of medium polarizability. a vacuum is the least polarizable medium (= 1).

Protein interior: 2-20.

water much more polarizable ( 80, for isolatedH20).

Thus, the environment is a stabilizing factor forbiopolymer structure. long-range interactions greatly weakened in Aq.

solution.


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Conclusion

In this Lecture we have discussed: Some basic definitions. The structural hierarchy of biological molecules:

1o

through 4o

structure.

The difference between the related terms: configuration and conformation. Here, we focus on biopolymer conformation.

The various molecular interactions which determinemacromolecular structure: Bonding interaction (covalent). Non-bonding interactions (weak).

Including the effect of the intervening medium ().

In the next Lectures, we begin our discussion of biopolymer structure with:

A discussion of Cellular Environments, An Introduction to concepts of Symmetry

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Lecture 1 - Introduction to Biological Macro Molecules

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