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16.3 Announcements
• Simulation project due November 7
Here, E0 (rN ) and E1 (rN ) refer to the two reference states, and the value of λ interpolates the
system potential energy function between that of E0 for λ = 0 and E1 for λ = 1. We can now write
the derivative of the Helmholtz free energy with respect to λ as follows:
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University of Wisconsin-Madison Lecture 16
CBE 710, Fall 2019 - Prof. R. C. Van Lehn October 29, 2019
∂F (λ) ∂
= −kB T ln Z(λ) (16.3)
∂λ ∂λ
kB T ∂Z(λ)
=− (16.4)
Z(λ) ∂λ
Z
kB T ∂
drN exp −βEλ (rN )
=− (16.5)
Z(λ) ∂λ
R N
dr ∂Eλ (rN )/∂λ exp −βEλ (rN )
= (16.6)
Z(λ)
N
∂Eλ (r )
= (16.7)
∂λ λ
This expression shows that we can relate the change in the free energy of the system with respect
to the coupling parameter to an ensemble average of that derivative sampled from an ensemble at a
particular value of λ, as indicated by the subscript in the angular brackets. We can then calculate
the complete free energy difference between system 0 and 1 by:
λ=1
∂Eλ (rN )
Z
F (λ = 1) − F (λ = 0) = dλ (16.8)
λ=0 ∂λ λ
This final integral is why the technique is called thermodynamic integration. In practice, this
integral is evaluated by choosing several discrete values of λ, sampling particle configurations ac-
cording to the potential energy function Eλ , and for each sampled configuration calculating the
energy using Eλ±dλ where dλ is some small interval. The derivative is approximated from a finite
difference between these three values and used to calculate the ensemble average. The integral is
then evaluated by quadrature. This approach does not necessarily require a linear coupling param-
eter, although in practice this is a simple method that is commonly used. It should be noted that
the coupling parameter approach, and the division of the thermodynamic integral into multiple
discrete values of λ, can also be used with free energy perturbation to improve convergence.
Given the similarities to free energy perturbation, thermodynamic integration is often used for
similar systems. It has been used extensively in calculating the phase behavior of self-assembled
mixtures, in part because thermodynamic integration can be used to calculate the free energy
between two phases that differ in their thermodynamic properties, such as temperature, via appro-
priate selection of a coupling parameter (as opposed to biasing their potential energies).
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University of Wisconsin-Madison Lecture 16
CBE 710, Fall 2019 - Prof. R. C. Van Lehn October 29, 2019
only scratching the surface of molecular simulations - other topics of interest include methods for
maintaining a constant pressure in simulation, methods for sampling systems in the grand canonical
ensemble, alternative free energy calculations that do not rely on predefined reaction coordinates,
etc. The Frenkel and Smit textbook does continue with several of these topics if you wish to pursue
them on your own.
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University of Wisconsin-Madison Lecture 16
CBE 710, Fall 2019 - Prof. R. C. Van Lehn October 29, 2019
one and only one stable equilibrium state for each simple subsystem. In the limiting condition, the
entire system is said to be at equilibrium.
Postulate 2 then tells us that equilibrium states are reached if a system is observed for a
sufficiently long amount of time - that is, each simple system (or simple subsystems in a composite
system) evolves toward a unique equilibrium state. Postulate 2 is only defined for an isolated
system with a given set of internal restraints. Changing the internal restraints (i.e., removing the
activation barrier in the previous example) will change the unique equilibrium state of the system
in a predictable way (i.e., the system components may undergo a reaction). This observation
underscores the importance of understanding and identifying internal restraints in the system.
Finally, note that in composite systems, the equilibrium state of the entire system cannot be
specified by only two independent variables, but each simple subsystem can be defined by two
independent variables. The properties of the composite system are thus defined by the collected
properties of the subsystems.
Since Postulate 1 and 2 together introduce the concept of stable equilibrium states that are
reached after the time-evolution of a system, we now must introduce the concept of a thermody-
namic process. A process defines the changes in the thermodynamic properties of a system that
occur when a system has an interaction with the environment or internal restraints are removed or
altered. The process includes a description of the two equilibrium end states, prior to and after the
process, the interactions occurring at the boundaries of the system, and the set of states through
which the system evolves, also known as the path. A path can be quasi-static, meaning that all
intermediate states in a process are equilibrium states that can be described with two independently
variable parameters. Processes that involve non-quasi-static paths pass through non-equilibrium
states that may require additional properties to be specified, and thus do not obey Postulate 1.
Various types of processes can be defined. For example, an isothermal process is one in which the
temperature is constant. More examples will be provided as we continue our studies. Postulate
2 specifies that the time evolution of a system to an equilibrium state must occur with no effect
on the environment, implying that the system is isolated. However, processes can also consist of a
series of steps, with individual steps affecting the environment; the net effect across multiple steps
must just be zero.
Postulate 3: For any states, (1) and (2), in which a closed system is at equilibrium, the change
of state represented by (1) → (2) and/or the reverse change (2) → (1) can occur by at least one
adiabatic process, and the adiabatic work interaction between this system and its surroundings is
determined uniquely by specifying the end states (1) and (2).
This postulate defines several important pieces of terminology that require some investigation.
First, we formally define the concept of work, which we have already used repeatedly in our study
of statistical mechanics. Following typical mechanical definitions, the work, W , is defined as the
product of a generalized force, f , multiplied by a generalized displacement, ∆x:
W = f ∆x (16.9)
dW = f dx (16.10)
Z x2
W = f dx (16.11)
x1
In its most general form, the product of the force and displacement would be a vector product
between a force vector f~ and a vector displacement; we drop this notation for simplicity.
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University of Wisconsin-Madison Lecture 16
CBE 710, Fall 2019 - Prof. R. C. Van Lehn October 29, 2019
As in statistical mechanics, we will define the sign convention such that the work is positive
if work is done on the system by the environment. In general, for all work interactions, the work
done on a system by the environment is equal to the work done on the environment by the system;
this is a consequence of Newton’s 3rd law and reflects the conservation of energy.
Next, we will define an adiabatic work interaction as an interaction between two closed
systems that does not involve a transfer of heat to the environment. Since we have not yet formally
defined heat, we can define adiabatic work interactions in terms of an observable experiment -
namely, adiabatic work interactions can be performed by the rise and fall of weights in an external
gravitational field connected by a frictionless pulley, which we know to be a system described
entirely by the work due to gravity. Examples of adiabatic work interactions include compressing
a gas with a piston on a frictionless surface, which could be accomplished by raising or lowering a
weight attached to the piston, or resistively heating a liquid by doing electrical work, which could
be accomplished by tying a rope attached to a weight around a motor and using the motor to send
current through a resistor that is inserted in a fluid. In each case, the gas/liquid container is a
closed system on which work is done.
With these definitions, let us now consider the meaning of Postulate 3. The postulate states
that while it may not always be possible to go from state (1) to state (2) solely via adiabatic work
interactions - i.e., via an adiabatic process - it will always be possible to either go from state (1) to
(2) via an adiabatic process or from state (2) to (1) by an adiabatic process. For example, consider
a gas in state (1) specified by P1 , T1 and state (2) specified by P2 , T2 . Suppose that the gas is in a
closed system with a piston that controls the system volume. If the gas is expanded adiabatically,
the pressure drops from P1 → P2 and we would observe that the temperature changes (this is due
to the relationship between energy and temperature for an ideal gas) To obtain a temperature T2 ,
we could add an electric generator to the system that is powered by a weight; assuming frictionless
wires, this allows us to heat the system to temperature T2 with the piston fixed such that the
pressure is maintained at P2 . This is thus a multistep adiabatic process from state (1) to (2) since
the walls and each step is adiabatic. Moreover, the inverse process is not possible, since we cannot
cool the system adiabatically by returning heat to the electric generator.
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University of Wisconsin-Madison Lecture 16
CBE 710, Fall 2019 - Prof. R. C. Van Lehn October 29, 2019
Since an adiabatic process is possible between any two states, Postulate 3 then defines the
internal energy of the system, U , as a derived parameter (i.e. one that is not directly mea-
surable) equal to the work done during an adiabatic process, since the adiabatic work is only a
function of the end states:
U 2 − U 1 = W 1→2,adiabatic (16.12)
Technically, this expression defines the change in the total energy of the system, including
the kinetic energy associated with center-of-mass motion in a system, potential energy associated
with body forces (i.e. gravity), and the internal energy associated with molecular motions (i.e.
translational degrees of freedom, vibrations, rotations), intramolecular effects (electron spin), and
intermolecular interactions. We will ignore the first two effects and treat the total energy as the
internal energy due to usage of this nomenclature throughout our study of statistical mechanics.
So, in total, Postulate 3 defines the internal energy as a derived parameter that is a function of
the states of two stable equilibrium systems. We refer to such a parameter as a state function.
Note that only changes in energy are meaningful; we could assign an energy to each state, but only
the energy change will matter.
While Postulate 3 states that two states can be connected by an adiabatic process, in principle
we can define any process, adiabatic or non-adiabatic, between the two states and the change in
total energy will be unchanged (since it is uniquely defined as the work done along the adiabatic
path). This observation leads to our definition of heat: heat is the difference in the total energy
change during a particular process and the actual work performed. We can write this as:
δQ = (U 2 − U 1 ) − δW (16.13)
= W adiabatic − W non-adiabatic (16.14)
∆U = δQ + δW (16.15)
This relation is referred to as the first law of thermodynamics - the change in the energy
of a system is always the sum of the heat (which is positive if heat is added to the system) and
the work (which is positive if work is done on the system by the surroundings) during a process.
Here we use the symbol δ to indicate that the associated parameter is path-dependent; while
the energy change is a fixed function of the initial and final state, the amount of heat and work
transferred depends on the path between the two states. Note that we will use the phrase “transfer
heat” but this just means that energy is transferred via a heat interaction - there is no heat that is
intrinsic to a state that is transferred. For a system to undergo a heat interaction, there must be
at least one non-adiabatic or diathermal wall, but having a diathermal wall does not imply that a
system will necessarily undergo a heat interaction.
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University of Wisconsin-Madison Lecture 16
CBE 710, Fall 2019 - Prof. R. C. Van Lehn October 29, 2019
Postulate 4: If the sets of systems A, B and A, C each have no heat interaction when connected
across nonadiabatic walls, then there will be no heat interaction if systems B and C are also so
connected.
This postulate effectively defines the concept of thermal equilibrium - systems connected across
non-adiabatic walls that do not have a heat interaction are at thermal equilibrium, and thus any two
systems that are connected to a third system that all experience no heat flow must have the same
temperature (which we have not strictly defined; suffice to say it is the quantity that its equivalent
for systems for which there is no heat transfer). This postulate thus requires the definition of the
temperature as an intensive parameter that is equal for two systems connected by nonadiabatic
walls that undergo no heat interaction.