BIBC 100 Structural BIOCHEM

An example of small molecular changes having large biological consequences

SICKLE CELL ANEMIA

Hemoglobin (carries O2 into our blood stream), genetic mutation causes a slight change in structure (single amino acid replacement), mutant hemoglobin aggregates to rigid strands, aggregated hemoglobin distorts red blood cells to a sickle shape

What are biomolecules shaped and organized by?

Weak, reversible, and noncovalent interactions

→biomolecules interact w/water, ions and small molecules, as well as other biomolecules

Polarity

Uneven electron distribution creates partial charges

-partial charges drive many noncovalent interactions

Entropy

Measure of molecular disorder/randomness

→molecules arrange in ways that increase the number of micro-states or overall freedom of motion

→helps explain why non polar groups cluster in water (when non-polar groups cluster together, fewer water molecules need to surround them, allowing more freedom of movement n increasing entropy)

Electronegatiivty

atoms differ in how strongly they pull shared electrons

→the more electroneg atoms like N or O can pull e- greater due to high electroned/e- affinity

→H ≈ C < N < O   

→ more electroneg atoms pull e- closer becoming partially negative, less electronegative atoms have less electron density and become partially positive      

Which elements created polar bonds in biomolecules?

O and N (due to high electronegativity)

What does every polar bond create?

A Dipole

Dipole

a pair of equal but opposite electric charges seperated by a small distance

→when e- are shared unequally, one side becomes slightly neg, the other becomes slightly pos

What does Molecular Polarity depend on?

Shape!!!

-a molecule can contain multiple polar bonds, whether the molecule is overall polar depends on whether or not the bond dipoles cancel or add together

What are the 4 properties of Water?

Solvent, Organizer, Reactant/Product, Thermal Buffer

→Bonus: ice form is less dense than liquid water (normal solids r denser than liquids), but ice floats helping aquatic environments remain habitable

Solvent Property of Water

dissolves ions and polar biomolecules

Organizing Property of Water

drives hydrophobic groups together and helps membranes/proteins assemble

Reactant/Product Property of Water

participates directly in biochemical reactions

Thermal Buffer Property of Water

stabilizes temperature bc of high heat capacity and heat of vaporization

Bonus Property of Water

ice form is less dense than liquid water (normally solids r denser than liquids but not in this case) Ice floats, helping aquatic environments remain habitable

Ranking electronegativity

H ≈ C < N < O

Do atoms share electrons equally?

No, more electroneg atoms typically pull e- closer and become partially negative, less electronegative atoms have less electron density and become partially positive

NonCovalent Interaction #1 Hydrogen Bonds

-type of dipole dipole interaction, arises from X-H bonds

-this bond forms when a partial + H covalently attahced to an O or N is attached to a nearby electron rich O or H

-this bond requires a donor AND an acceptor

Donors and Acceptors for Hydrogen Bonds

Donor: O-H or N-H

AcceptorL O or N with available electron density

is C-H considered an H-bond donor?

No bc this is nonpolar

Is every polar interaction a hydrogen bond??

NO

An H bond must directly involve a hydrogen atom

-the donor H is covalently bonded to O or N

-the acceptor is an electron rich O or N

-a covalent bond is not a hydrogen bond

Water and Hydrogen Bonding

-water can H bond with multiple neighbors

-each water molecule has 2 H bond donors and 2 H bond acceptors

-in liquid water, each H20 averages abt 3-4 H bonds

-the network is dynamic, H bonds constantly form and break

How many neighbors can water hydrogen bond with

4 neighbors

Unusual Water Properties Due to Weak Hydrogen Bonds

-individual H bonds r weak but many H bonds together make water highly cohesive

-Cohesion gives water unusually high melting point, boiling point, and heat of vaporization

-as a result water remains liquid across much of the temp change compatible with life

NonCovalent Interaction #2 Ion-Ion

attractions between opposite charges

-between inorganic ions: Na+ and Cl- in table salts

-btwn metal ions and anionic biological groups

→Mg2+... phosphate

    →Mg2+...COO-

    →Ca2+...COO-

-btwn oppositely charged biological groups: NH3+...COO- salt bridge in proteins

Ion-dipole interactions

-ions attract polar molecules

-an anion attracts the part pos end of the polar molecule, cation attracts neg end of polar molecule

What does water form since its polar?

it forms ion dipole interactions with dissolved ions, (process is called ion hydration)

Ion Hydration

water dissolves salts by hydrating ions

-from the example, the ion hydration (ion-dipole interaaction) weakens Na+…Cl- (ion-ion interaction) and disrupts the crystal lattice, leads to dissolution of NaCl

NonCovalent Interaction #3 Van Der Waals (London Dispersion)

-weakest interaction

-arise from transient dipoles: electron clouds fluctuate constantly, a temporary dipole in one atom can induce a dipole in a nearby atom, the two transient dipoles weakly attract each other, these interactions occur between all atoms at close range

-as two atoms move closer, their electron cloud will repulse each other and at a particular distance, repulsive force=attractive force, this distance= vanderwaal radius

Van der Waal Radius

defines closest noncovalent contact

-estimates how closesly another atom can approach without forming a covalent bond

-for two atoms, the preferred contact distance is approximately the sum of their van der waals radii

-if two nonbonded atoms are closer than this distance, their electron clouds repel creating a steric clash

Non Covalent Interaction #4 Hydrophobic Effect

clustering of non polar molecules in water

-one of the most important interactions in biology, a major driving force for protein folding and membrane assembly

Why does biology depend on hydrophobic effect?

because it drives proteins to fold by hiding nonpolar parts from water and causes cell membranes to form by clustering hydrophobic fatty acid tails together.

What does hydrophobic effect do?

clustering nonpolar surfaces releases ordered water and increases water entropy

Why is it important that non-covalent interactions exist in biology?

because they are dynamic and reversible meaning weak interactions allow biomolecules to assemble, disassemble, and respond to signals

Predicting molecular natures from chemical structures

When you see molecules rich in covalent bonds differing greatly in electronegativity (ex: O-H or N-H) you know that the molecule is soluble in water or hydrophilic (polar + charged)

When you see molecules with polar bonds o n one side (water soluble), nonpolar bonds on the other side (insoluble) → amphipathic (both hydrophilic and hydrophobic)

Hydrophilic molecules

polar + charged

-ex: biomolecules: sugars and organic acids (GLUCOSE good example)

interactions: all weak interactions except for hydrophobic ones

Hydrophobic molecules

nonpolar molecules

ex: biomolecules:waxes

Interactions: Hydrophobic, Van der Waals

Amphipathic Molecules

both hydrophobic and hydrophilic molecules

-Ex: biomolecules: some amino acids, phospholipids

Interactions: all noncovalent interactions

Whats something that non covalent interactions build?

Micelles and Lipid Bilayers

-they help with building membranes and folding proteins as well

Amphiphathic lipids

have hydrophilic head groups and hydrophobic tails

-hydrophilic heads interact favorably w water, hydrophobic tails force nearby water into ordered gages

How do noncovalent interactions drive protein folding?

they stablizie the folded protein by burying hydrophobic side chains away from water, leaving polar and charged side chains exposed on the protein surface, and forming H bonds, Ionic interactions, and van der Waal contacts +hydrophobic effect

What interactions collectively stabilize the folded state of a protein?

H bonds, ionic interactions, van der Waals contacts, and the hydrophobic effect.

What happens when nonpolar lipid tails cluster together?

they reduce exposed nonpolar surface, release ordered water to the bulk (polar head groups remain exposed to water), and favor spontaneous lipid assembly

-micelles and lipid bilayers form spontaneously

What is the result of lipid assembly?

Nonpolar tails cluster, polar heads remain exposed to water, and micelles/lipid bilayers form spontaneously.

Lipid assembly reduces…. ___

exposed nonpolar surface

Less non polar surface leads to…

fewer water cages → higher water entropy → favorable assembly

How do noncovalent interactions drive biomolecular binding?

biomolecules bind through many weak interactions across an interface

-each individual interaction is weak but together many contacts can create a stable complex

-more matching contexts= stronger and more specific binding

What do chemical groups (charged, polar, nonpolar, etc.) determine?

Interaction types

-they determine which interactions a molecules can make

pKa

constant describing the tendency of losing protons

Peptide bonds

covalent bonds that link AA residues to form polypeptides

What determines the physical properties and function of the protein

Amino acids and modifications

Proteins can be isolated based on their…

physical properties

Amino acids link covalently , then fold through _____ interactions

noncovalent

ex: amino acids is joined into a chain through covalent bonds, and then folds into a 3d shape due to non covalent interactions

What do all the amino acids share?

a common backbone

-the amino, carboxyl, and hydrogen groups are constant for every standard AA

-the side chain is whats unique

What do the side chains (R groups) vary in?

Structure, size, and polarity/charge

-R group determines identity/chemistry

α carbon (Cα)

this refers to the 1st carbon atom attached to the carboxyl group

How many α-AAs are chiral? And what is the exception?

19/20

Exception: glycine, because its R group is H making the molecule Achiral

What makes an molecule chiral?

-if it cannot be superimposed on its mirror image

-a common source of chirality is a carbon bonded to four different groups

-most AAs have a chiral C so they are chiral molecules

What type of amino acids do proteins use

L-amino acids

-chiral amino acids can exist as two mirror-image forms : L and D

-ribosomally synthesized proteins use L amino acids

-some D-amino acids occur in bacterial cell-wall peptides (but not in bacterial proteins)

Why do hydrophobic molecules cluster in water?

-water pushes them together (hydrophobic effect)

-clustering reduces how much hydrophobic surface touches water, which lets water molecules interact more normally w one another

-hydrophic molecules cluster to minimize their contact w water

Can nonpolar molecules experience van der waal interactions?

YES!

-even though they dont have permanent partial charges, their electrons r constantly moving, which can create temporary dipoles that attract nearby molecules

-polar molecules can also experience them, all molecules can have london disperson forces

What forces can nonpolar vs polar molecules experience?

Nonpolar: mainly london disperson forces

Polar: london disperson, dipole-dipole, hydrogen bonds if they have the right groups like O-H or N-H

Is a carbon bound hydrogen considered an H bond donor? (C-H)

NO!

-this is nonpolar

-carbon does not pull e- density away from hydrogen strongly enough for a typical hydrogen bond

What happens to the entropy of the surrounding water molecules during micelle formation?

-entropy increases

-when hydrophobic molecules form a micelle, they cluster together so less hydrophobic surface is exposed to water

-before micelle formation, nearby water molecules are forced into a more ordered arrangement around the hydrophobic parts

-after the hydrophobic parts cluster together, many of those water molecules are released and can move freely

What type of bond is a disulfide bond?

covalent bond

What are the 5 common AA side chain groups (R)? And how many are in each?

1)Nonpolar, aliphatic (7)

2)Aromatic (3)

3)Polar but uncharged (5)

4)Positvely charged (3)

5)Negatively charged (2)

AAs with nonpolar, aliphatic R groups

Gly (G), Ala (A), Pro (P), Val (V), Leu (L), Ile (I), Met (M)

-smallest is Gly (G)

-Pro=ring Rigid, strongly affects protein structure

-Leu and Ille have the same molecular weight

-Met is a thioether group (consists of a sulfur atom bonded to two carbon groups R-S-R)

AAs with aromatic R groups

Phe (F), Tyr (Y), Trp (W)

-these r groups are flat and bulky

-on Tyr (Somewhat polar), the hydroxyl group can form H bonds

-Tyr and Trp R groups absorbs UV light at ~280 nm.

-This is why most proteins absorb 280 nm light

AAs with polar, uncharged R groups

Ser (S), Thr (T), Cys (C), Asn (N), Gln (Q)

-these side chains tend to form H bonds

-hydroxyl groups present on Ser and Thr

-Cys has a sulfhydryl group (SH)

-Asn and Glnm contain amide groups (H2N=C=O)

AAs with positively charged (basic) R groups

Lys (K), Arg (R), His (H)

-all have an amino group, Lys has an NH3+, Arg has an NH2+. Histidine has a NH+

Lys: amino group mostly + charged at pH 7, Arg: guandinium group (pic included) mostly positively charged at pH 7, His: imidazole group (ring in photo) can switch between neutral and positive near pH 7

At or near physiological pH…____ are strongly basic; ____ is weakly basic and can change charge

Lys and Arg

His

Why is Histidine a special amino acid (pos charged R group)

-small pH changes can toggle His from charged to neutral or vise versa

-makes His USEFUL in enzyme catalysis and proton transfer

AAs with negatively charged (acidic) R groups

Asp (D), Glu (E)

-these r groups r mostly deprotonated at pH 7

-at low pH, these side chains become protonated (COOH) and lose their negative charge

-contain carboxyl groups (COO-)

How do we determine the charge of an amino acid???

Its protonation state

-protonation: gaining H+

-deprotonation: losing H+

Protonation effect on anion carboxyl group (COO-)

-turns an anion carboxyl group into a neutral group

COO- + H+ = COOH

Protonation effect on neutral amino group (NH2)

-turns neutral amino group to a cation group

NH2 + H+= NH3+

Ionization

a chemical group becomes charged by gaining or losing H+

Ionization of amino acids

-all amino acids undergo protonation or deportation resulting in changes in their net charge

-both the α-carboxyl and the α-amino groups can ionize

-the R group of some AAs can also ionize

-the protonation state of each group determines its charge and interactions

How do you determine the protonation state of a chemical group using pH and pKa?

pH high = H+ is low, so more deprotonation

pH low= H+ is high, more protonation

-lower pKa → Higher Ka → stronger acid → easier proton loss

pH

tells us the free proton concentration in the enviornment

pKa

tells us how easily a group loses H+

-deprotonation tendency

Ka

measures how much acid dissociates

Lower pKa = ___

easier proton loss (bc it would have a higher ka, making it a stronger acid)

To predict protonation state, compare _ and _

pH and pKa

-if ph=pka, 50 protonated, 50% deprotonated

-pka < pH , mostly deprontonated

-if pka > pH, mostly protonated

Higher pH means ____

fewer free protons, which means acid groups r more deprotonated

Compare pka and 7.4 to predict protonation

pka=7.4, 50% protonated 50% deprotonated

pka <7.4, mostly deprotonated

pka>7.4 , mostly protonated

What are the 3 possible ionizable groups of an amino acid?

alpha carboxyl group, alpha amino, and side chain (only for 7/20 of standard AA chave ionizable side chains)

What is the approximate pka of an α-carboxyl group?

2

At physiological pH (7.4), what is the charge of the α-carboxyl group?

predominantly deprotonated at ph 7.4

COO- , charge = -1

What is the approximate pka of the α- amino group?

9

At physiological pH (7.4), what is the charge of the α-amino group?

predominantly protonated at pH 7.4

(NH₃⁺), charge = +1.

Which 7 amino acids have ionizable side chains?

Asp (D), Glu (E), His (H), Cys (C), Tyr (Y), Lys (K), Arg (R).

-influences the net charge of the AA molecules

How does pH compared with pka determine protonation?

• pH <pKa: Protonated (holds H+)

• pH > pKa: Deprotonated (loses H⁺).

At physiological pH (7.4), what happens when pKa is less than 7.4?

Mostly deprotonated (lost H⁺).

At physiological pH (7.4), what happens when pKa is greater than 7.4?

Mostly protonated (kept H⁺).

What happens when pKa is near 7.4?

The protonation state is sensitive to small pH changes.

What are the side-chain pKa values of Asp (D) and Glu (E), and what are their charges at pH 7.4?

Asp = 3.65 and Glu = 4.25. Both are mostly negative (COO⁻).

What is the side-chain pKa of Lys (K), and what is its charge at pH 7.4?

pKa = 10.5. Mostly positive (NH₃⁺).

What is the side-chain pKa of His (H), and how does it behave at pH 7.4?

pKa = 6.0. Mostly unprotonated, but its protonation state can change with pH.

What can comparing pka to 7.4 help you predict?

Whether a group is mostly protonated or deprotonated

-pka below 7.4 means mostly deprotonated (Has lost H+)

-pka above 7.4 means mostly protonated (has kept H+)

-pka near 7.4 means sensitive to small pH changes