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

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

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:

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.

Analysis: Structural Properties

Separation of the centres of mass of the two peptides

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

Some Mekler-Idlis Pairs

CysArgGlySer

Ala

TrpGlyArgArg

Pro

SerAlaThrPro

Gly

CysAgrGlySer

Thr

Sense Complementary Sense Complementary

Biophyzika. 1969, 14, 581

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

Some Root-Bernstein Pairs

ArgArgArgArg

Ala

GlyGlyGlyGly

Pro

ProProProPro

Gly

CysCysTrpstop

Thr

Sense Complementary Sense Complementary

J. Theor. Biol. 1983, 100, 99

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.)