Aggregation of EPO Mimetic Peptide

1
Aggregation of EPO Mimetic Peptide
Erythropoietin (EPO) is a 166 a.a. cytokine that
regulates proliferation of Erythroid cells.
20 a.a cyclic peptide mimics action of EPO
GGTYSCHFGPLTWVCKPQGG
EPO mimetic aggregates ?molar range (active as
dimer)
Gilles Pieffet
2
Spontaneous Aggregation
EPO mimetic 40mM
20 ns
12 monomers 15000 SPC water timestep 2fs T
300K
Gilles Pieffet
3
Spontaneous Aggregation (low conc.)
EPO mimetic 10mM
45 ns
Gilles Pieffet
4
EPO mimetic Dimer 1
0 ns
10 ns
20 ns
30 ns
40 ns
Gilles Pieffet
5
Aggregation of EPO Mimetic Peptide
Gly tails
Dimer 1 (simulation 45 ns)
X-ray (receptor complex)
Gly tails

• Force field favors specific dimerization.
• Sampling hindered by formation of long lived
  metastable dimers.
• Preferred dimer differs from that in receptor
  complex.

Gilles Pieffet
6
Extended Simulations
intra
Pair 1 formed spontaneously
inter
intra
Pair 2 receptor bound structure
inter
Gilles Pieffet
7
Randomized Simulations of Pair 1
II
III
IV
V
VI
I
VI
V
randomize
IV
III
release (x 6)
II
I
equilibrate 200ns -gt sample 100ns
Almost no interchange in 2µs of sampling