David M. Smith Div. Org. Chem. and Biochem., Institut Ruđer Bošković, Zagreb
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Transcript of David M. Smith Div. Org. Chem. and Biochem., Institut Ruđer Bošković, Zagreb
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David M. SmithDiv. Org. Chem. and Biochem., Institut Ruđer Bošković, Zagreb
On the Characterization of Specific Interactions between Sense and Complementary Peptides: An Investigation Using Replica-Exchange Molecular
Dynamics
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The System
NH CH C
CH2
O
OH
NH CH C
H
O
HN CH C
H
O
HN CH C
CH2
O
HN CH C
CH2
HN
O
CH2
S
CH3
CH3C
O
H3C
HN CH C
CH
O
CH2
CH3
N
C
O
N
C
O
HN CH C
CH2
O
CH2
CH2
CH2
NH2
NH CH C
CH2
NH
O
OH
CH3
H3C
C
O
H3C
Ace-Tyr-Gly-Gly-Phe-Met-Nme
Ace-Ile-Pro-Pro-Lys-Tyr-Nme
Croat. Chem. Acta. 1998, 71, 591
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Replica Exchange Dynamics
Single simulations, especially in explicit solvent, are prone to become trapped in potential energy minima
Increasing the temperature can facilitate barrier crossingsbut can lead to irrelevant results
P(exchange) = exp -kBTi
1
kBTj
1Ei - Ej
A modern solution is to construct several replica simulationswith different temperatures and allow them to exchange according to:
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Replica Exchange Dynamics
16 replicas simulated for 10 ns each, implying 160ns in total.The temperatures range between 275K and 400K such that P≈0.2.
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Analysis: Structural Properties
Separation of the centres of mass of the two peptides
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Complementary Peptides: What are they ?
3’ ← AUA-CCC-CCG-AAG-UAC ← 5’Complementary mRNA (-)
5’ → TAT-GGG-GGC-TTC-ATG → 3’Sense DNA
3’ ← ATA-CCC-CCG-AAG-TAC ← 5’Complementary DNA
C ← Ile-Pro-Ala-Glu-His ← NComplementary Peptide
5’ → UAU-CCC-GGC-UUC-AUG → 3’Sense mRNA (+) Transcription
N → Tyr-Gly-Gly-Phe-Met → CSense PeptideTranslation
ChemBioChem. 2002, 3, 136
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Some Mekler-Idlis Pairs
CysArgGlySer
Ala
TrpGlyArgArg
Pro
SerAlaThrPro
Gly
CysAgrGlySer
Thr
Sense Complementary Sense Complementary
Biophyzika. 1969, 14, 581
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An Alternative Definition of Complementary Peptides:
3’ → AUA-CCC-CCG-AAG-UAC → 5’Complementary mRNA (-)
N → Ile-Pro-Pro-Lys-Tyr → CComplementary Peptide
5’ → TAT-GGG-GGC-TTC-ATG → 3’Sense DNA
3’ ← ATA-CCC-CCG-AAG-TAC ← 5’Complementary DNA
5’ → UAU-CCC-GGC-UUC-AUG → 3’Sense mRNA (+)
N → Tyr-Gly-Gly-Phe-Met → CSense Peptide
Pro. Nat. Acad. Sci. 1985, 82, 1372
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Some Root-Bernstein Pairs
ArgArgArgArg
Ala
GlyGlyGlyGly
Pro
ProProProPro
Gly
CysCysTrpstop
Thr
Sense Complementary Sense Complementary
J. Theor. Biol. 1983, 100, 99
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Molecular Dynamics: The Force Field
U(R) = bonds
Kr (r - req)2 angles
K ( - eq)2+
Bonds Angles
Dihedrals
Van der Waals Electrostatic
Vn
2dihedrals
(1 + cos[n - +
i<j
Aij
rij12
-
atomsBij
rij6
+qi qj
riji<j
atoms
+
+
+
Implicit Solvation (Elec.)
qi qj
f gb(rij,Ri,Rj)
i<j
atoms
+ + A+
Implicit Solvation (Non Elec.)