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Protein structure Amino Acids

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Component House Protein

Building Amino
Bricks
Blocks Acids
Journal of Chemical Information and Modeling ARTICLE
Adhesive Peptide
Concrete
Materials Bond
Sub- Living, Helices,
structure Bed room Strands
Iron Various
Skeleton
Structure interactions
Final 1BHK, Tertiary &
¨ R varies in size, shape, charge, hydrogen-
Structure 2BHK quaternary
bonding capacity and chemical reactivity.

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Figure 1. The ribbon diagram of the four representative protein structures used in the present study. They are referred by their unique PDB IDs, namely,
(A) 1FAZ, (B) 1UJ8, (C) 1UAI, and (D) 1NOA. This figure and subsequent molecular plots were created using UCSF Chimera package.76

the edge of the box was at least 15 Å. The TIP3P water model was the NPT ensemble. Finally the 30 ns MD run was initiated using
used for solvation.58,59 Counter ions were added to neutralize the the NPT ensemble which was considered as the production
system if needed. The total number of atoms in the system varied phase. The emergent trajectory was used for further analysis.
from 35266 to 56006. In all the simulations, periodic boundary Berendsen’s coupling algorithm was used for keeping the tem-
conditions (PBC) were employed in all three directions. The perature and pressure constant (P = 1 bar, τP = 1 ps, T = 300 K,
solvated structure was first energy minimized using the steepest τT = 0.05 ps).60 The temperature bath was separately coupled to
descent method, followed by conjugate gradient. Following mini- the solute and the solvent. Long range nonbonded interactions
mization, MD equilibration run was performed in two stages, were evaluated using the PME method and VDW interactions
initially with position restraints on the solute atoms for 1 ns using were calculated using a twin range spherical cutoff of 12 Å and
the NVT ensemble. In the latter half of equilibration, these re- 10 Å.61 A time step of 2 fs was used with the nonbonded list
strains were removed and another 1 ns run was carried out using update at every 10 steps together with the interactions within the
3210 [Link]/10.1021/ci200302q |J. Chem. Inf. Model. 2011, 51, 3208–3216

Amino Acids Peptide Bond

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Peptide Bond: Properties Primary structure

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¨ Linear amino acid sequence

¨ Determines all its chemical and biological properties
¨ Specifies higher levels of protein structure (secondary,
tertiary and quaternary)
q Most proteins contain between ~200 to ~500
residues

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Some Examples What do you do with the sequence?

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Histone (human) v Sequences of the same protein can be compared in

different species – yields a wealth of info on evolutionary
SETVPPAPAASAAPEKPLAGKKAKKPAKAAAASKKKPAGPSVSELIVQAASSSKERGGVSLAALKKALA pathways
AAGYDVEKNNSRIKLGIKSLVSKGTLVQTKGTGASGSFKLNKKASSVETKPGASKVATKTKATGASKKLK
KATGASKKSVKTPKKAKKPAATRKSSKNPKKPKTVKPKKVAKSPAKAKAVKPKAAKARVTKPKTAKPK v Sequences can be searched for the presence of internal
KAAPKKK
repeats
Rhodopsin (human) v Signals that determine the destination of proteins and
control their processing can be searched
MNGTEGPNFYVPFSNATGVVRSPFEYPQYYLAEPWQFSMLAAYMFLLIVLGFPINFLTLYVTVQHKK v Sequence data provide a basis for preparing antibodies
LRTPLNYILLNLAVADLFMVLGGFTSTLYTSLHGYFVFGPTGCNLEGFFATLGGEIALWSLVVLAIERYV
VVCKPMSNFRFGENHAIMGVAFTWVMALACAAPPLAGWSRYIPEGLQCSCGIDYYTLKPEVNNESF for a protein of interest
VIYMFVVHFTIPMIIIFFCYGQLVFTVKEAAAQQQESATTQKAEKEVTRMIIMVIAFLICWVPYASVAF
YIFTHQGSNFGPIFMTIPAFFAKSAAIYNPVIYIMMNKQFRNCMLTTICCGKNPLGDDEASATVSKTET v Sequences are valuable for making DNA probes that are
SQVAPA specific for the genes encoding the corresponding proteins

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Torsion Angle Torsion Angles: Peptide Backbone

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¨ Angle between two intersecting plans. ¨ Double bond nature of peptide bond
cause planar geometry
¨ Define rotation about a bond.
¨ Free rotation at N - Cα and Cα -
carbonyl C bonds
¨ Angle about the Cα - N bond is
denoted phi (𝛟) C(i-1)-N-Cα-C
¨ Angle about the Cα - C bond is
denoted psi (𝚿) N-Cα-C-N(i+1)
¨ The entire path of the peptide
backbone is known if all 𝛟 and 𝚿
angles are specified

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Not all Phi/Psi angles are possible Ramachandran Plot

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¨ Biophysicists Prof. G.
N. Ramachandran
constructed a space
filling model of
peptides and made
calculations to
determine which value
of 𝛟 and 𝚿 are
sterically permitted in
a polypeptide chain

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Ramachandran Plot for non-Gly Ramachandran Plot for Gly and

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and non-Pro residues 16
Pro residues

Gly Pro
Data from 500 high-resolution proteins

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Hydrogen bonding Secondary structures

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¨ A hydrogen bond occurs when two electronegative § 𝝰-Helix

atoms compete for the same hydrogen atom. § 3.6 residues per turn
§ Translation per residue 1.5 Å
§ Translation 5.4 Å per turn
¨ -D-H …A-
§ β-sheet
¨ Lengths and strengths of H-bonds depend on the § Polypeptide fully extended

electro-negativities of the acceptor and donor. § 2.0 residues per turn

§ Translation 3.4Å per residue

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𝝰-Helix Properties 𝝰-Helix Properties

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¨ Side chain groups point

outwards from the helix
¨ AA’s with bulky side
chains less common in
alpha-helix
¨ Glycine and proline
destabilizes alpha-helix
¨ Average Length is about

10-15 residues

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β-Strand β-Sheets
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¨ Polypeptide fully extended

¨ Stable when incorporated

into a β-sheet

¨ H-bonds between peptide

groups of adjacent strands

¨ Adjacent strands can be

parallel or antiparallel Antiparallel b-sheet Parallel b-sheet

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β-Sheets Parameters for Regular Secondary Structures

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Side chains point

¨
f y
alternately above and
below the plane of the Antiparallel b-sheet -139 +135
β-sheet Parallel b-sheet -119 +113
Right-handed a-helix -57 -47
310 -helix -49 -26
¨ 2- to 15 β-strands/β- p-helix -57 -70
Polyproline I -83 +158
sheet Polyproline II -78 +149
Polyglycine II -80 +150

¨ Each strand made of ~

6 amino acids

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Primary Structure Motifs

Simple combinations of a few secondary structural
elements with a specific geometric arrangement have
Secondary Structure been found to occur frequently in protein structures.
These units have been called super-secondary structures
or motifs.
Super Secondary Structure (Motif)
•Helix-loop-helix
•b-hairpin
•Greek key motif
•b-a-b motif Greek Key

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Helix-loop-helix motif

Parvalbumin Cro repressor

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EF hand Primary Structure

Secondary Structure

Super Secondary Structure (Motif)

Domains

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Domains Tertiary structure

§ Several motifs combine to form compact globular structures 55

called Domains ¨ Gives a specific overall

shape to a protein
§ The fundamental unit of tertiary structure is the domain
§A domain is defined as a polypeptide chain or part of a ¨ Involves various
polypeptide chain that can fold independently into a stable tertiary interactions (H-bonds,
structure Ionic, Hydrophobic
interactions ) and cross
§ Domains are also units of function link between different
part of the peptide
§ Often, the different domains of a protein are associated with chain
different function

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Hydrophobic Collapse Quaternary structure

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¨ Combination of two or
more tertiary units.
¨ Stabilized by the similar
interactions found in
tertiary structures.
¨ Hemoglobin consist of four
polypeptide chains.
¨ Transports oxygen in

blood.

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Importance of Protein Structures

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¨ The structure can provide clues to the function

through structural similarity with other proteins
¨ With a structure it is easier to guess the location of
active sites
¨ With a structure we can plan more precise
experiments in the lab
¨ We can apply docking algorithms to the structures
(both with other proteins and with small molecules)

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