Last class... To understand how living systems work, we need to - - PowerPoint PPT Presentation

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Last class... To understand how living systems work, we need to - - PowerPoint PPT Presentation

Mar 16, 2024 222 likes •632 views

Last class... To understand how living systems work, we need to focus at different levels to understand different aspects Knowledge of structure is very important

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SLIDE 1
  • Last class...
  • To understand how living systems work, we need to “focus” at

different “levels” to understand different “aspects”

  • Knowledge of structure is very important
  • “Native” structures of proteins: may be folded or unfolded
  • Static pictures and “molecular” dynamics
  • Conformational changes - Ca2+-ATPase example; also, folding

and unfolding of “linear” macromolecules

  • Conformational ensembles
  • Energy landscapes of molecules, assemblies, molecular

complexes, ...

  • Conformational states, substates, ...: regulation by modulation
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SLIDE 2
  • “Energetics” perspective

Unfolded Folded (protein, DNA, RNA) Monomers (homo/hetero) Oligomer(s) (protein, lipid) A + B A·B (binding) Conformation “a” Conformation “b” ∆ ∆ ∆ ∆G = ∆ ∆ ∆ ∆H – T ∆ ∆ ∆ ∆S

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SLIDE 3
  • Enthalpy and entropy

∆ ∆ ∆ ∆G = ∆ ∆ ∆ ∆H – T ∆ ∆ ∆ ∆S enthalpy changes (mainly: non-covalent interactions) entropy changes

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SLIDE 4
  • Outline
  • 1. Sequence - {Folding} - Structure - Dynamics - Function paradigm
  • 2. Molecular structure
  • 3. Steric effect or hard-sphere approximation
  • 4. Non-covalent interactions
  • 5. Entropy
  • 6. Stability and folding of proteins
  • 7. Lipids
  • 8. Binding

∆ ∆ ∆ ∆G = ∆ ∆ ∆ ∆H – T ∆ ∆ ∆ ∆S

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SLIDE 5
  • Outline
  • 1. Sequence - {Folding} - Structure - Dynamics - Function paradigm:

perspective for the course

  • 2. Molecular structure: representation, conformational

changes, conformational ensembles, conformer selection

  • 3. Steric effect or hard-sphere approximation: preferred (allowed)

versus not-preferred (disallowed) conformations; application to monosaccharides and peptides; Ramachandran map ... continued

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SLIDE 6
  • 3D structure at atomic level

X-ray crystallography Has made the most substantial contribution Provides static picture NMR spectroscopy Provides dynamic picture Size-limit is an issue (currently, up to 40-50 kDa) Molecular motions of 670 kDa 20S proteasome Nature 2007 445:618 3D structure has been determined by both the methods for some proteins: structure is not different

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SLIDE 7
  • www.rcsb.org

Protein Data Bank

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SLIDE 8
  • Nucleic Acid Database

http://ndbserver.rutgers.edu/

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SLIDE 9
  • Cambridge Crystallographic Database

www.ccdc.cam.ac.uk/

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SLIDE 10
  • Representing molecules
  • 1. Cartesian coordinates - most widely used
  • 2. Internal coordinates

The two are inter-convertible

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SLIDE 11
  • Representing molecules: Cartesian coordinates
  • (x,y,z) coordinates for each atom
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SLIDE 12
  • Cartesian coordinates
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SLIDE 13
  • Cartesian coordinates

X,Y,Z coordinates Amino acid residue number Amino acid name Atom name in Å units

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SLIDE 14
  • Internal coordinates

Also referred to as the “geometry” of the molecule

  • 1. Bond length (defined between two atoms)
  • 2. Bond angle (defined between three atoms)
  • 3. Torsion (or dihedral) angle

(defined with respect to four atoms) generally in Å units, some times in nm

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SLIDE 15
  • Bond length
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SLIDE 16
  • Bond angle
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SLIDE 17
  • Torsion angle
  • !

"#!$ %!%! $& $#' (( ! "#!$ %!%! $& $#' ((

Torsion angle: measure of rotation around a (single) bond

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SLIDE 18
  • Torsion angle
  • !

"#!$ %!%! $& $#' (( ! "#!$ %!%! $& $#' ((

If C1, C2, C3 and C4 are four consecutively bonded atoms, then the torsion angle is the angle between the normal to the plane containing the atoms C1, C2, C3 and the normal to the plane containing the atoms C2, C3, C4

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SLIDE 19
  • Torsion angle
  • )#$ $%#! *#+$$&*#!*$,! $#' !
  • $#''#.,%$&/"$$# $#'

%$ !". %

  • $#',%$&/"$$# $#'(

%$ !"' %!$& ' torsion: the twisting or wrenching of a body by the exertion of forces tending to turn one end or part about a longitudinal axis while the other is held fast or turned in the opposite direction (from the Merriam-Webster online dictionary)

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SLIDE 20
  • Torsion angle conventions

"%/0#1"%2 3 4%' 5 / $ 1$ !2 ) !6$#17#2 #"8,%#$ $%#!6 /#%$%.. + #+!$"#"8,% #$ $%#!6! $%. . +

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SLIDE 21
  • 12

12 172 172 12 12

  • Torsion angle nomenclature
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SLIDE 22
  • 9%,%! #!

$&→ → → →*#! :#, $& .%,

  • , 5

;#'$& .%,

Torsion angles and Newman projection diagrams

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SLIDE 23
  • sp3-sp3 torsion – possible definitions
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SLIDE 24
  • 9%,%!

#!$& → → → →*#! :#, $& .%,

  • , 5

;#' $& .%, < 7

Relationship between different definitions

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SLIDE 25
  • 9%,%!

#!$& → → → →*#!

:#, $& .%,

  • , 5

;#'$& .%,

  • Newman projection diagram: sp2-sp3 torsion
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SLIDE 26
  • 132
  • 9%,%!

#!$& → → → →*#!

:#, $& .%,

  • , 5

;#'$& .%,

  • Newman projection diagram: sp2-sp2 torsion
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SLIDE 27
  • =

3

  • N-Acetylmuramic acid (NAM)
  • 3
  • 9%,%! #!

$&→ → → →=*#!

:#, $&.%,

  • , 5;#'

$&.%,

β β β β-D-Glucose with N-Acetyl group, instead

  • f –OH, at C2 and D-lactic acid at O3

Newman projection: single substituent on a sp3

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SLIDE 28
  • viewed along the C-O bond (φ

φ φ φ1)

  • viewed along the O-C bond (ψ

ψ ψ ψ1)

Newman projection diagrams - examples

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SLIDE 29
  • >

> > > > > > > > > >

  • >

> > > > > ?"#+ #& .!+'*$&'+%!$&;#' $ 1'!$5'*#21@+!$% A% !+'*2

Schematic of AMP

Writing Newman projection diagrams

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SLIDE 30
  • B+%0

Define the torsion angle as C4-N9-C1’-O4’

  • >
  • >
  • >

> >

Writing Newman projection diagrams

For the N9-C1’ bond N9 is bonded to C4 and C8 C1’ is bonded to C2’, H1’ and O4’

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SLIDE 31
  • >
  • >

> >

  • Since N9 is sp2 hybridized,

C8 will be at 6 O’clock position

  • >

C%& %;%!&,$> 9 +1 *%$ %5"&#!2 !"(>% $>"#"8/#%$%#!

B+%0

Writing Newman projection diagrams

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SLIDE 32
  • >
  • >

> >

  • C/%"$>
  • %!","&#$#;%!$&%&

,%$&/"$$#($&% $#'%/ " $>"#"8/#%$%#!

Writing Newman projection diagrams

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SLIDE 33
  • >
  • >

> > %!">% &5*%%0(. +;#> !>,%* 7#1%!/!#!$&"#!;%+ $%#!2%( 71>"#"8/#%$%#!2 71>"#"8/#%$%#!2

  • >

> >

B+%0

Writing Newman projection diagrams

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SLIDE 34
  • B+%0
  • >
  • >

>

:#, $&.%,

  • , 5;#'

$&.%,

C4’-C5’ (phosphate)

>>

> > > > > >

:#, $&.%,

  • , 5;#'

$&.%,

>>>>

>

N9-C1’ (base with respect to ribose)

Newman projection diagrams - examples

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SLIDE 35
  • Conformation and configuration

Spelling: conformation, not confirmation Confirmation: process of supporting a statement by evidence Conformation: spatial arrangements of a molecule

Merriam-Webster online dictionary

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SLIDE 36
  • Conformation and configuration

Conformation and configuration Both refer to the spatial arrangement of atoms Change in configuration: breaking and remaking (in a different way) bonds Change in conformation: without breaking any bond change in bond length and bond angle (trivial) rotation about single bonds (most important)

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SLIDE 37
  • Prochiral carbon

CH2OH CHOH CH2OH CH2OH HCOH CH2OH CH2OPO3 HCOH CH2OH CH2OH HCOH CH2OPO3

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SLIDE 38
  • Cambridge Crystallographic Database

www.ccdc.cam.ac.uk/free_services/teaching/modules/teaching_webcsd/teaching_examp les_webcsd.1.1.html

www.ccdc.cam.ac.uk → → → → Free Services → → → → Teaching → → → → Click here for teaching modules

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SLIDE 39
  • Using CCDC’s Mercury for learning about chirality

Name Code Alanine LALNIN23 Alanine ALUCAL05 Toluene TOLUEN Lactic acid YILLAG Citric acid CITARC 2,2,2-Trifluoro-1-(9-anthryl)ethanol SOCLIF