Protein Structure, Function and Interactions Peptide-Protein Interactions Design of Peptides as Drugs

1
Protein Structure, Function and
InteractionsPeptide-Protein Interactions
Design of Peptides as Drugs
Burak Erman Chem. and Biol. Eng. Dept Koc
University, Istanbul Turkey
2
Overview Peptide-Protein Interactions The
simplest short range coarse graining The
neighborhood potential, contact map in native
proteins. Statistical thermodynamics of native
proteins. Fluctuations. Probability distribution
of fluctuations. The harmonic approximation The
Gaussian Network Model, GNM Energy-fluctuation
correlations in harmonic systems. Protein-ligand
interactions. The drug binding problem. Determina
tion of binding sites Energy gates of a protein
as the binding sites. Allostery. Graph
perturbation. Interaction pathways and hub
residues.
3
Peptide design Free energy changes upon binding.
Balance of different forces Entropy penalty.
Enthalpic interactions. Solvation entropy.
Different conformations of a peptide. Markov
statistics and calculating TD variables
4
The contact map
Residue Index
Residue Index
5
(No Transcript)
6
Physical interpretation Each pair of
residues in contact is connected with a linear
spring. Spring constants are same for each
spring. G is the spring constants matrix
We are interested in Fluctuations of residues
subject to the harmonic potential of the springs
7

• The system
• The protein and its environment form a closed
  system.
• Protein exchanges energy with the environment.
• Total energy of the protein surroundings
  constant.

8
Statistical thermodynamics of protein structure
and function Yogurtcu, O.N., M. Gur, and B.
Erman, Statistical thermodynamics of residue
fluctuations in native proteins. Journal of
Chemical Physics, 2009. 130(9) p. 095103-095113.
S The mean (thermodynamic) value of the
entropy, U energy, V volume, R position
vectors of Cas. The protein is in diathermal
contact with the surrounding water a pressure
(P) and a force (F) reservoir. The energy, volume
and the positions of residues exhibit
fluctuations.
Where
9
are the instantaneous extensive variables
The distribution
is the Massieu transform of the entropy
10
(No Transcript)
11
H. B. Callen, Thermodynamics and an introduction
to thermostatistics, Second ed. (Wiley, 1985).
12

• Harmonic Fluctuations

13
Higher order correlations
f is a higher order product of the fluctuations
of the extensive variables, DU, DV, DR.
Fk represents any of the extensive variables DU,
DV, DR, Yk represents the conjugate variables
1/T, P, F,
14
An increase in energy (protein taking energy from
surroundings) is correlated with large DRiJ2 A
decrease in energy (protein giving off energy to
the surroundings) is correlated with small
DRiJ2 The residues i and j with large DRiJ2 are
responsible for energy interactions.
These are the anticorrelated residue pairs.
15
Largest eigenvalue of the G matrix is
associated with the significant contribution to
DUi
DUi is the energy entering the protein from the
surroundings through residue i
16

• Those residues at the surface are the Energy
  Gates.
• Those residues that connect two surface gate
  residues constitute
• the Hubs along the Interaction Pathway.
• Those residues along the interaction pathway that
  are
• anticorrelated are the important ones.
• Connection to allostery is obvious.

17

• Example The HLA proteins B2705 (1OGT.pdb)

18
DUi
19
(No Transcript)
20
The change of residue at position 116 perturbs
the protein structure especially residue 101
We now perturb the connectivity of residue 101
and observe the resulting affinity changes
21
(No Transcript)
22
Haliloglu, T. and B. Erman, Analysis of
Correlations between Energy and Residue
Fluctuations in Native Proteins and Determination
of Specific Sites for Binding Physical Review
Letters, 2009. 102 p. 088103-088106. Haliloglu,
T., E. Seyrek, and B. Erman, Prediction of
Binding Sites in Receptor-Ligand Complexes with
the Gaussian Network Model. Physical Review
Letters, 2008. 100 p. 228102-4.
23
Overview Peptide design Different conformations
of a peptide. The free energy. Free energy
changes upon binding. Balance of different
forces Entropy penalty. Enthalpic
interactions. Solvation entropy. The neglected
part conformational changes of The peptide upon
binding
Markov statistics and calculating TD variables
24
Peptides are small proteins that consist of
5-15 amino acids
Peptides play a fundamental role in immune
recognition and induction of immune response
Jackson, D.C., et al., The central role played by
peptides in the immune response and the design
of peptide-based vaccines against infectious
diseases and cancer. Current Drug Targets, 2002.
3(2) p. 175-196.
25
Free energy changes upon binding
DFRB(L) change from rigid body translation and
rotation of the ligand,
DFconf(L) conformational free energy change of
the ligand
DFRB(P) change from rigid body translation and
rotation of the protein
DFconf(P) is from the conformational changes of
the protein,
DFbinding(LP) change in free energy due to the
interaction between the ligand and protein, and
DF(W) is the free energy change of water.
.
26

The ith residue of the peptide.

27

28
Ala, Glu, Lys, Met, Arg, Leu, Phe, Tyr, Trp
29
Ile, Val
30
XPr
31
Pro
32
Gly
33
(No Transcript)
34
We can obtain the probabilities from PDB
PX (fi, yi) NX(fi, yi)/ SNX(fi, yi)
PXY (yi, fi1) NXY (yi, fi1)/ SNXY
(yi, fi1)
35
(No Transcript)
36
References
Engin, O., M. Sayar, and B. Erman, Introduction
of Hydrogen Bond and Hydrophobicity Effects into
the Rotational Isomeric States Model for
Conformational Analysis o Unfolded Peptides.
Phys. Biol. , 2009. 6 p. 1-13.
Keskin, O., et al., Relationships between amino
acid sequence and backbone torsion angle
preferences in proteins. Proteins-Structure
Function and Bioinformatics 2004. 55 p.
992-998.
37
For a three state system
38
Statistical weight matrix
39
Partition function
40
Partition function
41
Helmholtz free energy, A E TS as
From this, we obtain the entropy as
42
Calculation of probabilities
43
Unal, E.B., A. Gursoy, and B. Erman,
Conformational energies and entropies of
peptides, and the peptide-protein binding
problem. Phys Biol, 2009. 6(3) p. 36014.
44
Entropy penalty
Mean conformational energy of the peptide
45
(No Transcript)
46
(No Transcript)
47
(No Transcript)
48
Number of possible peptide drugs of 10 residues
2010 1013
We have to choose the most suitable peptide from
this population
The entropy penalty seems to be a significant
factor in binding
Existing successful peptide drugs have low DS and
low Cv
49
Acknowledgments

• Mert Gur
• Osman Yogurtcu
• Besray Unal
• Ozge Engin
• Turkan Haliloglu
• Mehmet Sayar