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