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    Free Energy Calculation in MD Simulation

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    William Agudelo
    Free energy calculations in molecular dynamics (MD) simulations allow determining important thermodynamic quantities like binding affinities. The free energy can be calculated using experimental methods by measuring probabilities or work, or computationally using probability-based or thermodynamic integration methods. Challenges include insufficient sampling within finite simulations. Common computational methods include thermodynamic integration, free energy perturbation, umbrella sampling, and potential of mean force calculations along a reaction coordinate.

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    Free Energy Calculation in MD Simulation

    Uploaded by

    William Agudelo
    81 views49 pages
    Free energy calculations in molecular dynamics (MD) simulations allow determining important thermodynamic quantities like binding affinities. The free energy can be calculated using experimental methods by measuring probabilities or work, or computationally using probability-based or thermodynamic integration methods. Challenges include insufficient sampling within finite simulations. Common computational methods include thermodynamic integration, free energy perturbation, umbrella sampling, and potential of mean force calculations along a reaction coordinate.

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    Free energy calculations in molecular dynamics (MD) simulations allow determining important thermodynamic quantities like binding affinities. The free energy can be calculated using experimental methods by measuring probabilities or work, or computationally using probability-based or thermodynamic integration methods. Challenges include insufficient sampling within finite simulations. Common computational methods include thermodynamic integration, free energy perturbation, umbrella sampling, and potential of mean force calculations along a reaction coordinate.

    Copyright:

    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    81 views49 pages

    Free Energy Calculation in MD Simulation

    Uploaded by

    William Agudelo
    Free energy calculations in molecular dynamics (MD) simulations allow determining important thermodynamic quantities like binding affinities. The free energy can be calculated using experimental methods by measuring probabilities or work, or computationally using probability-based or thermodynamic integration methods. Challenges include insufficient sampling within finite simulations. Common computational methods include thermodynamic integration, free energy perturbation, umbrella sampling, and potential of mean force calculations along a reaction coordinate.

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    © All Rights Reserved
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    of 49

    Free Energy Calculation

    in MD Simulation

    Basic Thermodynamics

    Helmoholtz free energy


    A = U TS ! " #
    i
    $
    i

    dA = %
    re&
    're&ersi(le) const $ * T+ e, '--./+ Mc0uarrie 1 Simon

    2i((s free energy


    2 = U ! 3* TS ! " #
    i
    $
    i
    = H TS ! " #
    i
    $
    i
    d2 = %
    non3*
    're&ersi(le) const $ 3 T+ e, '--.45+ Mc0uarrie 1 Simon
    U internal energy 3 3ressure #
    i
    Chemical 6otential
    * *olume T Tem6erature
    S Entro6y dS = d,7T S = 8
    B
    ln 9

    :m6lication of Free Energy

    A ; B <
    e,
    = =A>7=B>
    <
    e,
    = e?6 '@A2
    B
    7CT+
    A2
    B
    = @CT ln <
    e,
    A2 = A2
    B
    ! CT ln 0
    A2 D B Unfa&ora(le
    A2 = B
    A2 E B Fa&ora(le

    Statistical Mechanics

    System can (e descri(ed using Hamiltonian


    H'6
    4
    )6
    -
    ).........6
    $
    ) r
    4
    ) r
    -
    ).......r
    $
    +

    Different ensem(le 'fi?ed system ,uantities+


    @ Canonical ensem(le '$)*)T+
    @ $3T ensem(le

    Statistical Mechanics

    Common Free Energy Ty6e

    Sol&ation Free Energy 7 Transfer Free Energy

    Binding Free energy

    Confomational Free Energy



    Calculating Free Energy

    E?6erimentally
    @ 6ro(a(ilities of finding the system at gi&en states
    A2 = @CT ln '3
    4
    73
    B
    +
    @ re&ersi(le %or8 of mo&ing the system (et%een
    t%o states

    Com6utationally
    @ 6o(a(ility
    @ re&ersi(le %or8 F more efficient

    3ro(a(ility Method ' Brute Force +

    Ergodic hy6othesis
    time a&erage = ensem(le a&erage

    A2 = @CT ln '3
    4
    73
    B
    +

    :s this trueG :n general) $HI


    @ sam6ling time is too short com6utationally
    @ hard to sam6le e&ery state of the system
    For system state of zero sam6ling) 3
    A
    = B F A2
    B F A
    = J

    A=lim
    t -
    1
    t

    A( t ) dt=
    1
    M

    M
    A
    i
    = A

    Alanine Di6e6tide





    Challenge

    Accurate calculations of a(solute free energy is


    nearly im6ossi(le due to insufficient sam6ling in a
    finite length and time scale simulation.

    $eed different methods to estimate free energy.

    Common method
    @ Thermodynamical integration
    @ Free energy 6ertur(ation
    @ Um(rella sam6ling
    @ 3otential of mean force

    Thermodynamic Cycle

    H ( x , p
    x
    , \)=H
    0
    ( x , p
    x
    )+\ H
    b
    ( x , p
    x
    )+(1\) H
    a
    ( x , p
    x
    )

    Thermodynamic :ntegration

    Thermodynamic :ntegration

    the &alue of EdA7dKD is accurately determined


    for a num(er of intermediate &alues of K) the
    total free energy is determined %ith numerical
    integration methods (ased on these &alues

    A'K+ is smooth enough and con&erged

    :ntermediate &aluesL
    fluctuation of MH7MK for each &alue of dA7dK

    Free Energy 3ertur(ation


    Error Estimation
    Chris Chi6ot N $AMD mailing list

    :n FE3) con&ergence may (e 6ro(ed (y monitoring the time@e&olution


    of the ensem(le a&erage. This is) ho%e&er) a necessary) (ut not
    sufficient condition for con&ergence) (ecause a66arent 6lateaus of
    the ensem(le a&erage often conceal anomalous o&erla6 of the
    density of states characterizing the initial and the final states. The
    latter should (e the 8ey@criterion to ascertain the local con&ergence of
    the simulation for those degrees of freedom that are effecti&ely
    sam6led.

    Statistical errors in FE3 calculations may (e estimated (y means of a


    first@order e?6ansion of the free energy) %hich in&ol&es an estimation
    of the sam6ling ratio of the latter of the calculation 'Straatsma) 4/O5+.
    htt6L77%%%.cirm.uni&@rs.fr7&ideos7-BB57e?6oses7B-PQeBris7Chi6ot.6df

    E?am6le

    Mutate 3HE to H:S


    3henylalanine Histidine

    F to H S9$T dU

    3henylalanine &s. Histidine


    A2
    3HE
    = @-.RST 8cal7mol
    A2
    H:S
    = @4.RTS 8cal7mol
    H
    U
    $
    CH C
    CH
    U
    HH
    H

    From amino acid S9$T free energy 6rofile) %e can estimate A2


    4
    and A2
    -

    L
    A2
    4
    = @-.RST 8cal7mol A2
    -
    = @4.RTS 8cal7mol
    AA2 = A2
    -
    @ A2
    4
    = +0.991 kcal/mol +0.991 kcal/mol

    From alchemical transformationL


    A2
    4
    alch
    = @-O.VO 8cal7mol A2
    -
    alch
    = @-R.OO 8cal7mol
    AA2W = A2
    -
    alch
    @A2
    4
    alch
    = +0.7 kcal/mol +0.7 kcal/mol
    1
    alch
    2
    alch 1 2 (aq)
    G
    (aq)
    G G
    1
    alch 2
    2
    alch 1 (aq)
    G
    (aq)
    G G G G SWNT - HIS HIS

    G G G G SWNT - PHE PHE
    2
    2
    alch
    1
    alch
    1
    =

    + = +

    To (e continued............

    Thermodynamic :ntegration

    H ( p
    1
    , p
    2
    , ....... p
    N
    , r
    1
    , r
    2
    , .......... r
    N
    )
    A A
    a-b
    =A((
    b
    )A((
    a
    )=

    dA(()
    d (
    d (
    dA(()
    d (
    =

    H ( r , p)
    (
    exH (r , p) dr dp

    exH (r , p) dr dp
    A A
    a-b
    =

    H ( r , p)
    (
    d (

    H ( r , p)
    (
    = F
    (
    =constraint force
    Ceaction Coordinate X

    Constraint force L force re,uired


    to constrain the system at a fi?
    reaction coordinate X

    E?am6le

    Translocation of C5B into D33C (ilayer

    Ceaction coordinate L Distance (et%een the


    CHM of C5B and CHM of D33C mem(rane

    SS constrained 6oints L B S- Y) 4 Y s6acing

    Harmonic constraint force

    8 = 4BB 8cal7mol7Y
    -


    Um(rella Sam6ling

    Sam6le %ith um(rella 6otential


    UZ'?+

    Com6ute (iased 6ro(a(ility


    3Z'?+

    Estimate un(iased free energy

    A ? = [8 ( )
    B
    T ln 3Z ? [ UZ ? F ( ) ( ) +

    F is undetermined (ut irrele&ant


    Com6le? surfaces ha&e multi6le (arriers

    $eed to 8no% the free energy surface to 8no% an efficient


    (ias

    Harmonic (iasing function

    Multi6le simulations

    3ut the minimum of the (ias in a different 6lace for each


    simulation 'sam6ling %indo%s+

    Estimate 3Z'?+ for each simulation

    Com(ine results from all simulations

    From one simulation


    A ? = [8 ( )
    B
    T ln 3Z ? [ UZ ? F ( ) ( ) +

    F de6ends on UZ'?+

    Different simulations ha&e different offsets

    $ot o(&ious ho% to com(ine different %indo%s




    9HAM

    9eighted Histogram Analysis Method

    Determines o6timal F &alues for com(ining


    simulations

    <umar) et al. \ Com6ut Chem) 4S) 4B44@4B-4)


    4//-

    2eneralizations
    Multidimension reaction coordinates
    Multi6le tem6eratures

    $
    sims
    = num(er of simulations
    n
    i
    '?+= num(er of counts in histogram (in associated %ith ?
    U
    (ias)i
    ) F
    i
    = (iasing 6otential and free energy shift from simulation i

    3'?+ = (est estimate of un(iased 6ro(a(ility distri(ution


    F
    i
    and 3'?+ are un8no%ns

    Sol&e (y iteration to self consistency



    Cunning US simulation

    Choose the reaction coordinate

    Choose the num(er of %indo%s and the (iasing


    6otential

    Cun the simulations

    Com6ute time series for the &alue of the


    reaction coordinate 'histograms+

    A66ly the 9HAM e,uations




    E?am6le

    Translocation of C5B into D33C (ilayer

    Ceaction coordinate L Distance (et%een the


    CHM of C5B and CHM of D33C mem(rane

    / %indo%s L B S- Y) T Y s6acing

    Harmonic constraint force

    8 = B.V 8cal7mol7Y
    -




    Hther Methods

    Steered MD

    Ada6ti&e Biased Force Method 'ABF+

    3arallel Tem6ering 'Ce6lica e?change+


    @ o&ercome free energy (arriers

    etc.

    Ce6lica E?change
    H&ercoming Free Energy Barrier

    $on@directed method
    'no reaction coordinate+

    Ho% to sam6le unfa&ora(le


    statesG

    At high T) (arriers are


    easier to o&ercome.

    Heat and cool the system


    to 6ush it o&er (arriers to
    sam6le ne% configurations

    Ce6lica E?change
    H&ercoming Free Energy Barrier

    Qaunch simulations at different


    tem6eratures

    S%a6 configurations (ased on a


    monte carlo criterion

    This criterion guarantees that the


    lo%est 'target+ tem6erature
    ]tra^ectory_ sam6les from the
    Boltzmann distri(ution.

    S%a66ing configurations
    effecti&ely im6ro&es sam6ling

    H&ercoming Free Energy Barrier

    9hen doing 6arallel tem6ering


    molecular dynamics) one must ta8e
    care in the inter6retation of the
    results. A 6arallel tem6ering e?change
    is an `un6hysicalW mo&e) and so one
    cannot dra% conclusions a(out
    dynamics. That is) %hen using 6arallel
    tem6ering molecular dynamics) one is
    only really doing a form of sam6ling
    and not `trueW molecular dynamics.
    Deem et al. 3hys . Chem. Chem. 3hys .
    - B B V ) R ) S / 4 B S / 4 5

    2arcia et al.
    3CHTE:$SL Structure)
    Function) and Bioinformatics
    V/LROSR/B '-BBV+

    Ceference

    Anna \ohansson
    ?ray.(mc.uu.se7acalle7mdP6hd7freePenerg.6df

    Da&id Mathe%s
    htt6L77rna.urmc.rochester.edu7teaching.html

    Chris Chi6ot
    htt6L77%%%.cirm.uni&@rs.fr7&ideos7-BB57e?6oses7
    B-PQeBris7Chi6ot.6df

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