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**Nuno Micaêlo, PhD
**

micaelo@quimica.uminho.pt http://simulation.quimica.uminho.pt

Universidade do Minho!, 2010

**Analysis of molecular dynamics experiments
**

!

Objectives

! Understand

that simulation studies is mostly about planning experiences and analysing your results ! Overview of some algorithms and analysis methods ! Learn how to validate and ensure the quality of your simulations

**Analysis of molecular dynamics experiments
**

!

**Output from molecular dynamics simulations
**

! Atom

coordinates trajectory (frequency 1 frame/ps) ! Energy, pressure, volume, temperature (frequency: same as coordinates) ! REMEMER: What we want is to have a collection of sates (conformation + energy of each conformation) ! Challenge:

" Explain

macroscopic observations with data obtained from atomic molecular simulations " Discover novel phenomena difficult or impossible to observe experimentally

**Analysis of molecular dynamics experiments
**

!

Visualization

! Gives

**you a first insight of your simulation ! Use your favourite visualization software
**

" Pymol " VMD " UCSF

(my favourite)

Chimera " Rasmol

! Advices

" Stick

to one (or two) software and learn all its features

This is important when you are developing parameters for new molecules ! Large conformational changes can be easily observed ! Short ranged interactions can be observed directly (hydrogen bonds. however you should try to quantify your observations . salt bridges) ! Structure visualization is important.Analysis of molecular dynamics experiments ! Visualization ! Observe the “time evolution” of your system ! See if geometries are as expected.

Check if your system is equilibrated by looking to the system’s potential energy. kinetic energy and total energy .Analysis of molecular dynamics experiments ! Potential energy ! It is the sum of all terms of the FF function.

Analysis of molecular dynamics experiments ! Density Easily compared with experimental data ! Some systems may need more or less time to converge towards the equilibrium ! .

Analysis of molecular dynamics experiments ! Atomic root mean square displacement (RMSD) ! Is an average distance between a conformation and a reference structure ! RMSD will depend on the atoms used for fitting ! Mass weighted RMSD .

Analysis of molecular dynamics experiments ! Atomic root mean square displacement (RMSD) 1 2 Configuration at t=n 3 Initial configuration (t=0) 4 5 .

angle and dihedral changes) but also whole molecule rotation and translation. we can eliminate the translation and rotational movement of our system using a fitting procedure.Analysis of molecular dynamics experiments ! Atomic root mean square displacement (RMSD) ! Molecules suffer conformational alterations (bond. ! The fitting methods translates and rotates the systems relative to a reference structure position and minimizes the RMSD between them. ! In most cases. .

Analysis of molecular dynamics experiments ! Fitting the conformation at time (t=n) against the initial structure (t=0) ! After fitting you can see more clear the conformational changes of your molecule 1 2 1 1 22 Before fitting After fitting 3 4 5 44 33 5 5 .

. . 6109-6116. Phys. W.Dashed line: simulation in water using the GROMOS87 force field 3) Solid line using the GROMOS96 force field van Gunsteren.. 108: p. 1998.Analysis of molecular dynamics experiments ! Atomic root mean square displacement (RMSD) Hen egg white lysozyme as a function of MD simulation. Chem.F. 1) Dashed line: simulation in vaccum using the GROMOS87 force field 2) Dot . Validation of molecular dynamics simulation. J.

Validation of molecular dynamics simulation. Phys. y and z axes ! It can give you a measurement of the size and “compactness” of your system ! Can be correlated with X-ray or NMR experimental data Hen egg white lysozyme as a function of MD simulation. 1) Dashed line: simulation in vaccum using the GROMOS87 force field 2) Dot . 6109-6116. 1998.Dashed line: simulation in water using the GROMOS87 force field 3) Solid line using the GROMOS96 force field van Gunsteren. 108: p. .. W. J..F. Chem.Analysis of molecular dynamics experiments ! Radius of gyration (Rg) ! Is the root mean square distance of the atoms about the molecule x.

Analysis of molecular dynamics experiments ! Radius of gyration (Rg) in one dimension 1 2 3 4 1 Rg = # rk " rmean N k =1 N ( ) 2 N is the number of atoms 5 ! .

continuum electrostatic calculations ! Two concepts " Accessible surface " Molecular surface . docking. to understand many molecular processes and properties: Solvation free energy.Analysis of molecular dynamics experiments ! Molecular Surface ! Important " Folding.

org/Science/Compchem/feature14. Molecular Surfaces.. Connolly.Analysis of molecular dynamics experiments ! Solvent accessible surface ! The solvent accessible surface is traced out by the probe sphere center as it rolls over the protein ! The surface is given by the center of the probe sphere.html . ML.netsci. http://www.

Phys.. Validation of molecular dynamics simulation. 1) Dashed line: simulation in vaccum using the GROMOS87 force field 2) Dot .Analysis of molecular dynamics experiments ! Solvent accessible surface Hen egg white lysozyme as a function of MD simulation..Dashed line: simulation in water using the GROMOS87 force field 3) Solid line using the GROMOS96 force field van Gunsteren. 6109-6116. J.F. W. 1998. 108: p. . Chem.

netsci. ML. Molecular Surfaces.org/Science/Compchem/feature14..html . http://www.Analysis of molecular dynamics experiments ! Molecular surface ! The molecular surface is the surface traced by the inward-facing surface of the probe sphere Connolly.

Analysis of molecular dynamics experiments ! Radial distribution function.. neutron diffraction Leach. X-ray. g(r). gives the probability of finding an atom at distance r from another atom ! The neighbors around each atom are sorted into distance bins. 2001: Prentice Hall. . Molecular modelling: principles and applications. g(r) ! Useful to describe the structure of a molecular system ! The pair distribution function. 2nd ed. NMR. A.R. and averaged over the entire simulation ! Can be compared with experimental data.

Analysis of molecular dynamics experiments ! Radial distribution function of the blue atoms around the red atom (1 angstrom shells). ! The number of atoms found on each shell is normalised with the expected number of atoms in that slice r r 0 1 2 3 n(r) 0 3 5 9 g(r) 0.shell thickness ( ) ! 1.4 2.1 g( r) = n ( r) / " 4 #r 2$r ! .shell radius "r .system density r .0 2.0 .

Analysis of molecular dynamics experiments ! Liquid and solid g(r) ! In the liquid state.2 Å than in the ideal solution ! Solids have long range structural ordering . it is two times more likely that two atoms are separated by 1.

Chem. Yashonath. Estimation of error in the diffusion coefficient from molecular dynamics simulations. Phys. 1997. 101(27): p. R. and S. . MSD ! The MSD contains information on the atomic diffusivity ! Provides an easy way to compute the diffusion constant Chitra. B. 5437-5445. J.Analysis of molecular dynamics experiments ! Mean square displacement.

. Oxford: Oxford University Press. D ! If the system is liquid. M.Analysis of molecular dynamics experiments ! Diffusion coefficient. and D. Computer simulation of liquids.P.J. 1997. Tildesley. MSD grows linearly with time ! Diffusion is calculated using the Einstein relation ! Can be compared with NMR data Allen.

J. Computer simulation of liquids.P. and D.Analysis of molecular dynamics experiments ! Shear viscosity. 1997. . results from the nonbonded intermolecular interactions ! Determined using the periodic perturbation method ! Can be compared with experimental data Allen. M. Tildesley. # ! Resistance of a fluid that is being deformed by shear stress ! In simple liquids. Oxford: Oxford University Press.

1997. Computer simulation of liquids. M. Oxford: Oxford University Press.P. a spatially periodic velocity profile is developed Allen. .J.Analysis of molecular dynamics experiments ! Periodic perturbation method ! Non-equilibrium MD simulation ! At each time step an external force in the x-direction is applied to each molecule ! As a result. and D. Tildesley.

Analysis of molecular dynamics experiments ! Clustering ! Clustering is very useful to group ‘similar’ molecular structures ! There is no correct algorithm for clustering ! Clustering methods rely on ‘similarity’ (or dissimilarity) measures between structures " RMSD between pairs of structures " Torsion angle ‘distance’ .

A. 2nd ed. .Analysis of molecular dynamics experiments ! Clustering methods ! Single " Add linkage a structure to a cluster when its distance to any element of the cluster is less than a specific cut-off (ex: 2 angstroms) " Fails in some cases Group 1 Group 2 Group 1 Leach.R. 2001: Prentice Hall. Molecular modelling: principles and applications..

Molecular modelling: principles and applications. . 2nd ed.Analysis of molecular dynamics experiments ! Clustering methods ! Jarvis " Uses Patrick a nearest neighbor approach " Two conformations are considered to be in the same cluster if they satisfy the following criteria: They are in each other’s list of m nearest neighbors " They have p (p<m) nearest neighbors in common " Leach.R. 2001: Prentice Hall.. A.

R. A..Analysis of molecular dynamics experiments ! Clustering methods ! Jarvis Patrick .Example " Three nearest neighbors (m = 3) " Two out of three nearest neighbors in common (p = 2) Leach. Molecular modelling: principles and applications. . 2nd ed. 2001: Prentice Hall.

$Hvap ! Energy required to overcome the intermolecular interactions in the liquid state ! Important to parameterize new liquids ! Calculated from the potential energies in the gaseous (Ugas) and liquid phases (Uliq).Analysis of molecular dynamics experiments ! Enthalpy of vaporization. Two simulations ! Easily compared with experimental data .

RMSF ! Measure of the deviation between the position of the atoms and some reference structure ! Locate regions with high/low mobility .Analysis of molecular dynamics experiments ! Root mean square fluctuation.

RMSF Active site loop .Analysis of molecular dynamics experiments ! Root mean square fluctuation.

Analysis of molecular dynamics experiments ! B-factors. B ! Calculated from RMSF ! Comparison with X-ray B-factors .

phenyl-ethanol NO catalysis of S! Transition state of 2.5 Å. Angle 30º.phenyl-propanol Catalysis R and S .Analysis of molecular dynamics experiments ! Hydrogen bonds ! Donor acceptor distance 3. ! Responsible for many short range molecular properties Catalysis of R Transition state of 1.

R. A value of 0 indicates no correlation and an absolute value of 1 indicates high degree of correlation Leach. Cxy ! Determines if two properties are correlated ! The correlation coefficient cxy between two data sets.. of the same size with M elements is given by: ! -1"cxy"1. X and Y. . 2nd ed. Molecular modelling: principles and applications.Analysis of molecular dynamics experiments ! Correlation function. A. 2001: Prentice Hall.

Analysis of molecular dynamics experiments ! Time correlation coefficients ! Determines if the value of one property a some instant y (0) is correlated with another property at latter time x(y) ! If the x and y properties are different. Molecular modelling: principles and applications. . 2001: Prentice Hall..R. Cxx(t) is referred as autocorrelation function Leach. Cxy(t) is referred as cross-correlation function ! If the x and y properties are the same. A. 2nd ed.

Analysis of molecular dynamics experiments ! Correlated data ! Example property time .

2nd ed.1) is called the correlation time. how well does the system “remember” its previous state. A. 2001: Prentice Hall. . or the relaxation time (tcorr) cxx 1 0.. Has initial value of 1 and decays to 0 (t!") ! The time taken to loose the correlation (cxx=0.Analysis of molecular dynamics experiments ! Autocorrelation function ! Determines ! -1"cxx"1.1 0 tcorr time Leach. Molecular modelling: principles and applications.R.

2001: Prentice Hall. 2nd ed. .Analysis of molecular dynamics experiments ! Correlation time/Relaxation time ! Your simulation must be longer than the correlation time of the property you are interested to measure ! Longer simulations provide better correlation time statistics by using different (M) time origins (tj) Leach. A.. Molecular modelling: principles and applications.R.

. 1997. data collected at very short intervals could be correlated. for some properties. computer simulation experiments are subject to systematic and statistical errors ! Most of the time we want to calculate the average of some property B over a finite data set (energy. Oxford: Oxford University Press. Tildesley. we would like to know the variance of this distribution ! However. Computer simulation of liquids. and D.J. variance will be underestimated Allen.Analysis of molecular dynamics experiments ! Estimating errors ! As in real experiments. M. density) ! Assuming that our data is normally distributed. If this happens.P.

Analysis of molecular dynamics experiments ! Estimating errors ! Example Correlated data Uncorrelated data .

if the value of property X is statistically independent from the previous one. Tildesley. and D.Analysis of molecular dynamics experiments ! Estimating errors ! In a trajectory with M frames. Computer simulation of liquids. Oxford: Oxford University Press.J. the variance of the mean is given by: were %2 Allen. 1997. .P. M.

Oxford: Oxford University Press. 1997. Computer simulation of liquids. . the variance is underestimated and must be corrected ! In this context. Tildesley.J.Analysis of molecular dynamics experiments ! Estimating errors ! However.P. and D. M. if our data has a correlation time (tcorr) higher than 1. this means that only about one configuration in every tcoor steps recorded contributes with new information to the average Allen.

energies) ! Learn and study how microscopic properties can explain the observed experimental facts. C) .Analysis of molecular dynamics experiments ! Other analysis ! The analysis of you data can be one of the most time consuming steps of your research projects ! Most of the properties you want to analyse are “buried” in the simulation output (trajectory. ! Write your own software analysis tools (python. awk.

Validating your simulations Establish a clear working hypothesis and research plan. W.. it means that: ! ! A new phenomenon has been found.. then simulate ! You must ensure that your simulations are valid ! Just because the atoms move doesn't mean that the simulation is well done! ! If the result of a simulation is novel. Chem. J. Phys. unexpected or strange. 108: p. Validation of molecular dynamics simulation. Think first. 6109-6116.F. AND/OR ! The results are wrong van Gunsteren. 1998. .

108: p... Phys. .Validating your simulations ! The results could be wrong because: ! The model is inappropriate ! The force field is inadequate ! The results have not converged due to poor sampling ! The software contain bugs ! The software was used incorrectly van Gunsteren. W.F. J. Validation of molecular dynamics simulation. 1998. 6109-6116. Chem.

Validation of molecular dynamics simulation.Validating your simulations ! Agreement between simulation and experiment can be the result of: ! The simulation adequately reflects the experimental system ! The property examined is insensitive to the details of the simulation ! Error compensation van Gunsteren. W.. 6109-6116. J. Phys. .. 1998. Chem. 108: p.F.

1998.. Validation of molecular dynamics simulation. . J. 108: p. Phys. Chem.Validating your simulations ! No agreement between simulation and experiment can be the result of: ! The simulation does not reflect the experimental system " Model " Force field " Sampling/convergence " Software bug " Incorrect software usage ! The experimental data are incorrect van Gunsteren. W.F.. 6109-6116.

. Chem.F..Validating your simulations ! Publishing ! Refer to the theory and methodologies used ! Refer the force field used. Phys. version and modifications ! Present the time evolution/correlation of key properties in order to judge the degree of sampling and convergence ! Refer to the software used. J.. 108: p. 6109-6116. Validation of molecular dynamics simulation. version and modifications ! Specify the chosen input parameters of the simulation van Gunsteren. 1998. W.

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