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Protein Structure & Drug Design

(Ref/text: Biochemistry Zubay, etc)

Course content:

1. Protein structure, stability, folding

2. Protein structure prediction

3. Bioinformatics in Drug Discovery &Development guest lecturer

How does the aa sequence encode the 3D structure?

DNA mRNA protein

hierarchies of protein structure diagram

2nd law of Thermodynamics systems at const temp

& press find an equilm state that is a compromise

between comfort (low enthalpy,H) and freedom

(high entropy, S), to give the minimum Gibbs free

energy G = H-TS

(T = abs temp)

interxn of mainchain & sidechain, w one another, w

the solvent, restriction of sidechain mobility,

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determine the relative stabilities of different

conformation

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native state where the folding pattern is

thermodynamically stable significantly better than

other conformations

PROTEIN STABILITY & FOLDING

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rotation permitted around the N-C & C -C single bonds

(except proline)

angles and define the conformation of residues

2 atoms cannot occupy the same space limits values of

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conformational angles (allowed regions)

Allowed regions generate standard conformations -

helices & -strand/sheets std/pre-fab structures

stabilized by weak intrxns H bonds, betw main chain atoms

wool - -helices, silk - -sheets

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globular proteins contain several helix and/or sheet regions,

connected by turns/loops

The Sidechains

sidechains offer the physicochem versatility to generate all

foding patterns. Vary:

* SIZE smallest gly (H atom), largest phe, benzene ring

* ELECTRIC CHARGE bear net +/- charge @ normal

pH.

Asp, Glu -ve charged

Lys, Arg +ve charged

salt bridges attractive airwise intrxns between charged

residues of opposite pairs

* POLARITY form H bonds to other olar sidechains, or to

mainchain, or water

hydrophobic protein interiors contribute to stability

Hydrophobic Effect

* SHAPE & RIGIDITY shape of sidecahin depends on

its chem. Strc & or degrees of internal conformational

freedom

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Motifs & Domains

Recap, basic unit of structure -helix & -strand/sheet

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Motif combination of a few secondary structure elements w

specific geometric arrangements

+ used again & again indifferent protein structure

3 common motifs:

1. Helix-loop-helix

2. Hairpin motif

3. - - motif

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1. Helix-loop-helix motif

(a) associated w DNA-binding proteins

(b) associated w calcium-binding proteins

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2. Hairpin motif

- loop length, 2 5 aa

- efficient way to form tight loop

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3. - -motif

- right-handed crossover betw 2 parallel sheets, where the

connecting region consists mainly of -helix

Domain basic unit of tertiary structure

combination of2 or more structural motifs

some proteins contain a single domain

others contain 2 or more domains, held together by

covalent or non-covalent lingkages

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Example 1 domain structures (H-loop-H motif)

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PROTEIN STRUCTURE DETERMINATION

X-ray Crystallography

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InteractiveBraggs law & Diffraction applet:

http://www.eserc.stonybrook.edu/ProjectJava/Bragg/index.html

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http://www.eserc.stonybrook.edu/ProjectJava/Bragg/index.htmlhttp://www.eserc.stonybrook.edu/ProjectJava/Bragg/index.html

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