(=polymers) Term favored by chemistscontents.kocw.net/KOCW/document/2014/hanyang/bertbinas/6.pdf ·...

Macromolecules

(=polymers)

Term favored by biologists

Term favored by chemists

Polymers are chain-like molecules made of monomers

Today, we will talk about • What kinds of macromolecules exist • How they are made • How their structure is related to their functions

Copyright © 2007 Pearson Education Inc., publishing as Pearson Benjamin Cummings

Giant Molecules from Smaller Building Blocks

• Macromolecules are synthesized by dehydration reactions (=condensation reactions)

(Condensation reaction)


• When macromolecules are degraded, the process is reversed: this is called hydrolysis .

• There are three main categories of bio-macromolecules:

– Glucose monomers Polysaccharides (탄수화물)

– Amino acid monomers Proteins (단백질)

– Nucleotide monomers Nucleic acids (핵산)

– (Lipids do not form polymers, they rather interact by hydrophobic interactions)


Polysaccharides • Polysaccharides are polymers of glucose .

– Three main forms: starch, glycogen, cellulose

= Carbohydrates =

• Why is glucose so special amongst the sugars? – Since glucose has the most stable conformation

Starch granules (electron microscopy)

Starch

Amylose (helix)

Amylopectin (tree)

Amylose

Amylopectin

• Starch is a plant polysaccharide. – Potatoes and grains (wheat, corn, rice) – Plant cells store starch for energy. – Starch is a mix of amylose and

amylopectin

• Glycogen is an animal polysaccharide. – similar in structure to starch, but more highly branched. Also unlike starch, glycogen is

synthesized using a specialized protein as a seed point. – Most abundant in liver and muscle cells, used as rapid energy source

(α 14)

Glycogen granule (with seed protein in the center)

Glycogen

http://en.wikipedia.org/wiki/Glycogen


• Is the most abundant organic compound on Earth. – forms cable-like fibrils in the walls that enclose plants. – is a major component of wood.

• glucose monomers are linked in different orientation (β 1 4 bond) than in starch and glycogen Straight, rigid, insoluble in water Animals cannot break down cellulose (cows do only with the help of symbiotic bacteria)

Cellulose

Cellulose fibers

Macrofibril

Microfibril

Chains of cellulose molecules

β 1 4

α 14

α 14

Summary: The key difference between starch, cellulose, and glycogen is how the glucose monomers are connected

1

2 3

4

5

6


• Proteins are polymers made from up to 20 different amino acids. • Proteins are the functionally most versatile type of macromolecules in the cell

•Structural Proteins •Storage Proteins •Contractile Proteins •Transport Proteins •Defensive Proteins

•Receptor Proteins •Enzymes •Hormonal Proteins •Sensory Proteins •Gene Regulatory Proteins

(hair, horn, feather, spider web, connective tissue, tendon)

(seed, egg)

(muscle)

(hemoglobin)

Proteins


• Synthesis of proteins: Condensation of amino acids creates peptide bonds.

N-terminus (the beginning of a

protein)

C-terminus (the end of a protein)

The peptide bond

• Protein synthesis is costly and energy-consuming since each additional monomer must be selected out of 20 possibilities – each kind of protein has a unique amino acid sequence

• The largest known protein is the muscle protein titin

• 26,926 amino acids, chemical formula is C132983H211861N36149O40883S693

• 1 micrometer long

• The body has tens of thousands of different kinds of protein. – The arrangement of amino acids makes each one different

• A typical polypeptide consists of more than 100 amino acids

Number of proteins sharing each possible number of amino acid residues (all ~20,000 proteins of the worm C. elegans)

• Proteins have four levels of structure – Primary – Secondary – Tertiary – Quaternary


•Primary structure = The amino acid sequence

Example: lysozyme (an enzyme)


• A change in the primary structure of a protein will often affect its higher-order structure and therefore the function.

– The substitution of one amino acid for another in hemoglobin causes sickle-cell disease (겸상적혈구 빈혈증)

• The abnormal hemoglobin molecules tend to crystallize, deforming some of the cells into a sickle shape

•Secondary structure – Local pattern or local structure within certain stretches of polypeptide – Alpha (α)-helix, pleated sheet, or absence of structure (=random coil) – H-bonds confer stability of the secondary structures

• Tertiary structure = “the protein fold” – The overall three-dimensional shape of the protein

•Quaternary structure

• A structure made from two or more subunits (= individual polypeptides)

What Determines Protein Structure?

An amino acid chain usually folds spontaneously to form the shape for that protein

• Driving forces for folding: Hydrophobic interactions, H-bonds, ionic interactions, disulfide (S-S bridges).

http://en.wikipedia.org/wiki/Protein_folding

In the aqueous milieu of the cell, hydrophobic amino acids tend to “hide” inside proteins, hydrophilic (polar) amino acids tend to be on the surface of the protein.

At abnormal pH, high temperature, or increased concentrations, proteins may unfold (“denaturation”)

Hydrophilic amino acid Hydrophobic amino acid

But

• Most amino acid sequences would not make sense, would not fold reasonably

• Existing proteins comprise only a tiny part of the theoretical sequence space

The difference between an arbitrary amino acid sequence and a real protein

A typical protein has at least 100 amino acids

• There are 20100 (~ 10130) possibilities to form a protein that is 100 amino acids long:

10,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000,000

• For each amino acid sequence, there is theoretically a huge number of folding pathways, but most of them would lead to a dead end

─ What is/are the physical rule/s according to which proteins fold?

─ Considering the huge number of possible ways to fold and the dead ends, how can proteins fold fast and correctly?

─ Can we write a computer algorithm to calculate the three-dimensional structure based only on knowledge of amino acid sequence?

• The folding problem is not solved yet

─ However, based on the know structural motifs (X ray crystallography), reasonable predictions can be made

─ This is called the semi-empirical approach

The “folding problem”

• In a few cases for very short amino acid sequences, computer models have almost solved the folding problem

http://www.sciencemag.org/content/338/6110/1042.full

http://www.opm.phar.umich.edu/

Pick an example molecule, click Jmol program to open (will open in new window), and go through different views

• In most cases the semi-empirical approach is taken, especially for membrane proteins (which are difficult to crystallize)

Example: Sodium-potassium pump (maintains the dis-equilibrium of Na and K ions)

Example: Aquaporin-4 (channel that allows water to flow in and out of the cell)

Misfolding

•Real proteins often “try” several folding pathways and often end up misfolded.

•For large proteins, specialized proteins assist the folding process.

•Misfolded proteins are not only useless but dangerous because they expose hydrophobic patches and aggregate Cells have clean up mechanisms.

•Even though the different proteins are present at very different concentrations in the cell, these concentrations are usually just below the concentration at which they would aggregate.

•Folding diseases are frequent and often associated with aging.

http://www.mpg.de/19212/Protein_folding

Norrby E., Prions and protein-folding diseases. J Intern Med. 2011 Jul;270(1):1-14. doi: 10.1111/j.1365-2796.2011.02387.x.

Example of folding disease: Prion diseases • In prion diseases a protein named prion protein (PrP) sometimes assumes a different

conformation with more beta sheets, which favors aggregation. • Prion diseases are “infectious”: Aggregates of misfolded PrP can induce normal PrP to

join the aggregate and also misfold. • Prion diseases are deadly and cannot be cured yet. • This example also shows that at least in some cases, ONE amino acid sequence can

determine more than one stable, well-defined conformation.

Normal PrP (mainly alpha-helical)

Misfolded PrP (more beta sheets)


• Nucleic acids are mainly information storage molecules.

– They provide the directions for building proteins.

• There are two types of nucleic acids:

– DNA, deoxyribonucleic acid (only information storage)

– RNA, ribonucleic acid (more versatile molecules)

Nucleic acids


• Nucleic acids are polynucleotides = polymers of nucleotides • Nucleotide monomers are linked into long chains = DNA strands. • Two complementary DNA strands form a double helix


• RNA, ribonucleic acid, is slightly different from DNA. – Its sugar has an extra OH group. – It has the base uracil (U) instead of thymine (T).

– Unlike DNA(which always forms a double helix), RNA can form complex tertiary structures

tRNA rRNA

A ribozyme

• The fact that RNA can form tertiary structures is of major importance in biology • Since it can form complex tertiary structures, RNA can have protein-like function (non-

informational functions)

This is the most complex macromolecular structure presently known. It is called a ribosome. The ribosome has a weight of 2.7 million Daltons and consists of 57 different proteins and 3 large RNA molecules. The picture shows that the ribosome consists of two large subunits (grey/blue and brown). In the larger subunit: RNA – grey Protein – blue Also, the ribosome temporarily binds another RNA molecule (green)

In the living cell, macromolecules are rarely swimming alone, but form higher-order complexes

Why DNA is the universal information storage molecule

The information density of biological macromolecules

Example: a small “macro”-molecule that consists of only 6 units

• Nucleic acids (A, T, G, C): 46 (~ 4,000) different hexanucleotides possible

• Proteins (20 different amino acids): 206 (64 000 000) different hexapeptides possible

• Sugars: with 20 different units (counting different possibilities to branch), 1.44 x 1015 hexameric oligosaccharides are possible.

The biological significance of the high information density of sugars has only begun to be studied.

If proteins or sugars have a higher information density than DNA, why is DNA the hard drive of the cell?

Requirements for a hard drive are

• Sufficient information density (RNA, DNA, proteins, sugars)

• High chemical stability (DNA, some proteins, some sugars)

• Easy copy mechanism (RNA, DNA)

• Easy reading mechanism (RNA, DNA)

Only DNA fulfills ALL of these criteria

Information content should not affect structure of storage device (no branching or folding)

Summary of structure-function relationships of macromolecules

• Polysaccharides: Structural and energy storage functions low complexity requires

only 1 type of building block (glucose, the most stable of the hexoses)

• Proteins: Highly diverse executor functions Highly diverse secondary and tertiary

structures need relatively large set of building blocks (20 amino acids)

• DNA: Only informational role uniform secondary structure regardless of

informational content minimal number of building blocks (4 nucleotides)

• RNA: Mixed (sub-optimal) informational and functional roles intermediate

complexity of structure achieved by chemical modifications of nucleotides

Summary – Macromolecules (biopolymers)

•Bio-Macromolecules are formed from monomers (M) through condensation reactions: • (M)n-OH + H-(M) + energy (M)n+1 + H2O (Initiation, elongation, termination). •The reactions can often be reversed, allowing monomers to be recycled.

•Lipids do NOT form polymers •They aggregate via hydrophobic interactions into droplets (“fat”) or films (see lecture on membranes).

•The most abundant polysaccharides Cn(H2O)n are polymers of glucose. •Starch and glycogen are polymeric storage forms of glucose in plants and animals, respectively. Glucose units are arranged in tandem (α 14) (plus some branching), and the polymers form granules. •Cellulose: Glucose units are arranged in tandems with alternating orientation (β 14), and the polymers form cables with mainly a structural function. Cellulose cannot be digested by animal cells.

•Proteins are polymers of amino acids connected by peptide bonds (-CO-NH-). •Proteins are “executor molecules”, fulfilling all imaginable functions. •Only a tiny fraction of the theoretical sequence space forms stable structures. Real proteins form stereotypic secondary structures (α helix, β strand) and elaborate higher-order structures. •Protein structures cannot yet be calculated ab initio but good semi-empirical approaches exist. •Also, the folding problem is not solved yet. Misfolding is frequent and often leads to diseases.

•Nucleic acids are polymers of nucleotides containing desoxyribose or ribose. •DNA (desoxy) is made of A, T, G, and C units forming an extremely long helical structure that does not depend on the nucleotide sequence. DNA is stable and optimized for storing, reading, copying information. •RNA is made of A, U (instead of T in DNA), G, and C units forming shorter (compared to DNA) chains. RNA can fold into diverse secondary and tertiary structures and therefore can fulfill also “executor” (protein-like) roles. RNA is much less stable than other macromolecules.

• 생체 고분자들은 축합반응을 통해 단위체(M)로부터 형성된다.

• (M)n-OH + H-(M) + 에너지 → (M)n+1 + H2O (개시, 신장, 종료). • 이 반응들은 종종 가역적으로 될 수 있으며, 이에 따라 생성된 단위체들은 재활용된다.

• 지질류는 중합체을 형성하지 않는다.

• 이들은 소수성 상호작용을 통해 작은 물방울들 (“지방”) 또는 얇은 막 형태 (membrane 강의 참조)로 응집된다.

• 가장 풍부한 다당류 Cn(H2O)는 포도당의 중합체이다.

• 전분과 글리코겐은 각각 식물과 동물에서 포도당 중합에 의한 보관형태이다. 포도당이 (α 1→4) 나란히 정렬되며(또한 곁가지로도), 중합체들은 알갱이를 형성한다. • 셀룰로즈: 포도당이 (β 1→4) 교대식으로 일렬로 정렬되며, 중합체들은 대부분 구조적 기능을 가진 케이블 형태를 만든다. 셀룰로즈는 동물세포에 의해 분해되지 않는다.

• 단백질은 펩타이드 결합 (-CO-NH-)에 의한 아미노산의 중합체이다.

• 단백질은 “집행 분자”로서, 상상 가능한 모든 기능들을 수행한다. • 이론적인 서열공간(선형)에서 안정적인 구조를 형성할 수 있는 부분은 매우 작다. 실제 단백질은 공간형태적인 이차구조 (α helix, β strand)와 정교한 고차 구조를 형성한다. • 단백질 구조들은 아직 이론적으로 예측할 수 없으나, 좋은 반·경험적인 접근법이 존재한다. • 단백질 접힘 또한 아직 해결되지 않았다. 접힘 실수(misfolding)는 빈번하며, 종종 질병을 유발한다.

• 핵산은 디옥시리보즈 또는 리보즈를 포함하고 있는 뉴클레오타이드의 중합체이다.

• 산소 원자 하나가 없는 DNA는 A, T, G 그리고 C 개체들로 구성되며, 염기서열에 관계없이 매우 긴 나선구조를 형성한다. DNA는 안정적이며, 정보의 저장, 읽기, 복제에 최적화 되어있다.

• RNA는 A, U (DNA의 T 대신), G, 그리고 C로 구성되며, 짧은 사슬 (DNA와 비교하였을 때)을 형성한다. RNA는 다양한 이차와 삼차 구조들로 접힐 수 있으며, 결과적으로 “집행자”의 역할 (단백질과 같이) 또한 수행할 수 있다. RNA는 다른 거대분자들에 비해 덜 안정적이다.

요약- 거대분자 (생체고분자)

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