Specific interactions between sense and complementary peptides what can molecular dynamics tell us
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Specific Interactions Between Sense and Complementary Peptides: What Can Molecular Dynamics Tell Us?. David M. Smith Div. Org. Chem. and Biochem., Institut Ruđer Bošković, Zagreb. Sense Peptide. N → Tyr-Gly-Gly-Phe-Met → C. Translation. Sense mRNA (+). 5’ → UAU-CCC-GGC-UUC-AUG → 3’.

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Specific interactions between sense and complementary peptides what can molecular dynamics tell us
Specific Interactions Between Sense and Complementary Peptides:What Can Molecular Dynamics Tell Us?

David M. Smith

Div. Org. Chem. and Biochem., Institut Ruđer Bošković, Zagreb


Complementary peptides what are they

Sense Peptide Peptides:

N → Tyr-Gly-Gly-Phe-Met → C

Translation

Sense mRNA (+)

5’ → UAU-CCC-GGC-UUC-AUG → 3’

Transcription

Complementary DNA

3’ ← ATA-CCC-CCG-AAG-TAC ← 5’

Sense DNA

5’ → TAT-GGG-GGC-TTC-ATG → 3’

Complementary mRNA (-)

3’ ← AUA-CCC-CCG-AAG-UAC ← 5’

C ← Ile-Pro-Ala-Glu-His ← N

Complementary Peptide

Complementary Peptides: What are they ?

ChemBioChem.2002, 3, 136


Some mekler idlis pairs
Some Mekler-Idlis Pairs Peptides:

Sense

Complementary

Sense

Complementary

Cys

Arg

Gly

Ser

Ser

Ala

Thr

Pro

Ala

Gly

Trp

Gly

Arg

Arg

Cys

Agr

Gly

Ser

Pro

Thr

Biophyzika.1969, 14, 581


Hydropathicity and the molecular recognition theory

Hydrophilic Peptides:

Hydrophobic

Hydrophobic

Hydrophilic

Hydrophilic

Hydrophilic

Hydrophobic

Hydrophobic

Hydropathicity and the Molecular Recognition Theory

Biochem. Biophys. Res. Commun.1984, 121, 203


An alternative definition of complementary peptides

Sense Peptide Peptides:

N → Tyr-Gly-Gly-Phe-Met → C

Sense mRNA (+)

5’ → UAU-CCC-GGC-UUC-AUG → 3’

Complementary DNA

3’ ← ATA-CCC-CCG-AAG-TAC ← 5’

Sense DNA

5’ → TAT-GGG-GGC-TTC-ATG → 3’

Complementary mRNA (-)

3’ → AUA-CCC-CCG-AAG-UAC →5’

N → Ile-Pro-Pro-Lys-Tyr →C

Complementary Peptide

An Alternative Definition of Complementary Peptides:

Pro. Nat. Acad. Sci.1985, 82, 1372


Some root bernstein pairs
Some Root-Bernstein Pairs Peptides:

Sense

Complementary

Sense

Complementary

Arg

Arg

Arg

Arg

Pro

Pro

Pro

Pro

Ala

Gly

Gly

Gly

Gly

Gly

Cys

Cys

Trp

stop

Pro

Thr

J. Theor. Biol.1983, 100, 99


The system
The System Peptides:

Ace-Tyr-Gly-Gly-Phe-Met-Nme

Ace-Ile-Pro-Pro-Lys-Tyr-Nme

Croat. Chem. Acta.1998, 71, 591


Molecular dynamics the force field

Bonds Peptides:

Angles

Dihedrals

Van der Waals

Electrostatic

Implicit Solvation (Non Elec.)

Implicit Solvation (Elec.)

Molecular Dynamics: The Force Field


Molecular dynamics in practise
Molecular Dynamics in Practise Peptides:

In principle, doing MDs is simply a matter of solving Newton’s equations of motion

In practise we must numerically integrate these equations with a finite time step (typically 1-2 fs)


Molecular dynamics in action
Molecular Dynamics in Action Peptides:

50 ps of MD at 300 K with implicit solvation


Analysis structural deviations
Analysis: Structural Deviations Peptides:

Root Mean Square Deviation from a reference structure vs time


Analysis clustering

Cluster 1, Pop. = 28% Peptides:

<E> = -57.5 kcal/mol

Cluster 2, Pop. = 45%

<E> = -58.6 kcal/mol

Backbone

Overlay

Cluster 3, Pop. = 27%

<E> = -58.5 kcal/mol

Minimum Energy Structure

E= -16.7 kcal/mol

Analysis: Clustering


Analysis clustering1
Analysis: Clustering Peptides:

28%

45%

Implicit solvent, 150 ns

27%


Principle component analysis
Principle Component Analysis Peptides:

Projections onto the eigenvectors of the covariance matrix


Principle component analysis1
Principle Component Analysis Peptides:

28%

45%

What about the force field?

FF94, Implict solvent, 150 ns

27%


Differences in the force field
Differences in the Force Field Peptides:

12%

27%

FF99, Implict solvent, 150 ns

4%

58%


Differences in the force field1
Differences in the Force Field Peptides:

51%

33%

FF03, Implict solvent, 150 ns

16%


What does experiment say

NMR, experiments in binary bilayered mixed micelles Peptides:

(bicelles) show a well-defined structure:

Biophys. J.2004, 86, 1587

What Does Experiment Say

NMR experiments in water show an essentially random

distribution of conformers


Explicit solvation
Explicit Solvation Peptides:

50 ps of MD at 300 K with explicit solvation (NVT)


Explicit solvation analysis
Explicit Solvation: Analysis Peptides:

54 %

27%

19%

40 ns of MD at 300 K with explicit solvation (FF03)


Replica exchange dynamics

A modern solution is to construct several replica simulations

with different temperatures and allow them to exchange

according to:

Replica Exchange Dynamics

Single simulations, especially in explicit solvent, are prone

to become trapped in potential energy minima

Increasing the temperature can facilitate barrier crossings

but can lead to irrelevant results


Replica exchange dynamics1
Replica Exchange Dynamics simulations

16 replicas simulated for 2.5 ns each, implying 40ns in total.

The temperatures range between 275K and 420K such that P≈0.2.


Replica exchange dynamics2
Replica Exchange Dynamics simulations

27%

40%

33%

40 ns (16 x 2.5) of MD at 275-420 K with explicit solvation (FF03)


Non exchanging replicas
Non-Exchanging Replicas simulations

Replica exchange MD is an inherently parallel method

An alternative approach is to construct several non-

interacting replicas (distributed computing)

An efficient way to implement this is to first run one

simulation at high temperature and to cluster the results

The structure closest to the centroid of each cluster can

then be used as a starting point for each replica


Non exchanging replicas1
Non-Exchanging Replicas simulations

30%

37%

33%

40 ns (8 x 5) of MD at 300 K with explicit solvation (FF03)


Sense and complementary peptides
Sense and Complementary Peptides simulations

1 ns of MD at 300 K with explicit solvation


Sense and complementary peptides1
Sense and Complementary Peptides simulations

19%

30%

16%

23%

13%

40 ns (8 x 5) of MD at 300 K with explicit solvation


A closer look at the clusters
A Closer Look at the Clusters simulations

Cluster 1: Population 30 %


A closer look at the clusters1
A Closer Look at the Clusters simulations

Cluster 2: Population 19 %


A closer look at the clusters2
A Closer Look at the Clusters simulations

Cluster 3: Population 23 %


A closer look at the clusters3
A Closer Look at the Clusters simulations

Cluster 4: Population 13 %

Cluster 5: Population 16 %


Analysis structural properties
Analysis: Structural Properties simulations

Separation of the centres of mass of the two peptides


Analysis structural properties1
Analysis: Structural Properties simulations

Separation of the centres of mass of the complementary residues


Conclusions
Conclusions simulations

  • The force field can have a strong influence on the structural

  • properties. FF03 can probably be trusted.

  • Non-interacting replicas constitute a good approximation to

  • the replica exchange method and a good alternative to a single

  • long simulation, at least for small peptides.

  • Met-enkephalin does not have a well-defined native structure

  • in aqueous solution at 300 K.

  • Met-enkephalin does exhibit some affinity for its complementary

  • counterpart but this is apparently not based on the specific

  • interactions predicted by the Molecular Recognition Theory.


Analysis clustering ff03

Cluster 1, Pop. = 51% simulations

<E> = 0.4 kcal/mol

Cluster 2, Pop. = 33%

<E> = -0.5 kcal/mol

Backbone

Overlay

Cluster 3, Pop. = 16%

<E> = 0.4 kcal/mol

Minimum Energy Structure

E= -16.7 kcal/mol

Analysis: Clustering (ff03)


Analysis clustering ff031
Analysis: Clustering (ff03) simulations

51%

33%

16%


Principle component analysis ff03
Principle Component Analysis (ff03) simulations

51%

33%

16%