Energy

functions and their relationship

to molecular conformation

CS/CME/BioE/Biophys/BMI 279
Oct. 3 and 5, 2017
Ron Dror
 Outline
• Energy functions for proteins (or biomolecular
systems more generally)
– Definition and properties
– Molecular mechanics force fields
• What does the energy function tell us about
protein conformation?
– The Boltzmann distribution
– Microstates and macrostates
– Free energy
 Energy functions for proteins
(or biomolecular systems more generally)
 Energy functions for proteins
(or biomolecular systems more generally)

Definition and properties

 Energy function
• A potential energy function U(x) specifies the
total potential energy of a system of atoms as a
function of all their positions (x)
– For a system with n atoms, x is a vector of length 3n
(x, y, and z coordinates for every atom)
– In the general case, include not only atoms in the
protein but also surrounding atoms (e.g., water)
Energy (U)

Energy (U)

Position Position
Position
 Relationship between energy and force
• Force on atom i is given by derivatives of U with
respect to the atom’s coordinates xi, yi, and zi
F(x) = −∇U(x)
• At local minima of the energy U, all forces are zero
• The potential energy function U is also called a
force field
Energy (U)

Energy (U)

Position Position
Position
Types of force fields (energy functions)
• A wide variety of force fields are used in atomic-
level modeling of macromolecules
• Physics-based vs. knowledge-based
– Physics-based force fields attempt to model actual
physical forces
– Knowledge-based force fields are based on statistics
about, for example, known protein structures
– Most real force fields are somewhere in between
• Atoms represented
– Most realistic choice is to model all atoms
– Some force fields omit waters and other surrounding
molecules. Some omit certain atoms within the protein.
 Energy functions for proteins
(or biomolecular systems more generally)

Molecular mechanics force fields

 Molecular mechanics force fields
• Today, we’ll focus on molecular mechanics force
fields, which are often used for molecular
simulations
• These are more toward the physics-based, all-
atom end (i.e., the more “realistic” force fields)
– Represent physical forces explicitly
– Typically represent solvent molecules (e.g., water)
explicitly
• We’ll revisit the forces acting between atoms and
write down the functional forms typically used to
approximate them
 Bond length stretching
• A bonded pair of atoms is effectively connected
by a spring with some preferred (natural) length.
Stretching or compressing it requires energy.

Energy
Natural bond
length (b0)

U (b) = kb ( b − b0 )
2

Note: A factor of 1/2 is sometimes included in

this equation. I’m ignoring such constant
factors (they can be folded into kb or the units). Bond length (b) 10
 Bond angle bending
• Likewise, each bond angle has some natural value.
Increasing or decreasing it requires energy.

Energy

Natural bond
angle (θ0)

U (θ ) = kθ (θ − θ 0 )
2
Bond angle (θ) 11
 Torsional angle twisting
• Certain values of each torsional angle are
preferred over others.

Energy
60° 180° 300°(−60°)

U (φ ) = ∑ kφ ,n ⎡⎣1+ cos ( nφ − φn ) ⎤⎦
Torsional angle (Φ)
n
Typically n takes on one or a few values between 1 and 6 (particularly 1, 2, 3, 6) 12
 Torsional angle twisting
• Certain values of each torsional angle are
preferred over others.

Energy

U (φ ) = ∑ kφ ,n ⎡⎣1+ cos ( nφ − φn ) ⎤⎦
Torsional angle (Φ)
n
Typically n takes on one or a few values between 1 and 6 (particularly 1, 2, 3, 6) 13
http://images.slideplayer.com/38/10813003/slides/slide_34.jpg
 Electrostatics interaction
• Like charges repel.
Repulsive Opposite charges attract.
r

- -
• Acts between all pairs of
atoms, including those in
different molecules.
• Each atom carries some
Energy
“partial charge” (may be
a fraction of an
elementary charge),
r which depends on which

+ - Attractive
atoms it’s connected to

U (r) =
qi q j
r
where qi and qj are partial
Separation (r) charges on atoms i and j
14
 van der Waals interaction
• van der Waals forces act
r between all pairs of atoms
and do not depend on
charge.
• When two atoms are too
close together, they repel
Repulsive strongly.
• When two atoms are a bit
further apart, they attract
Energy

one another weakly.

Energy is minimal when atoms are
Attractive “just touching” one another

Separation (r) 15
 van der Waals interaction
r
Aij Bij
U ( r ) = 12 − 6
r r
We can also write this as:
Repulsive
⎡⎛ r0 ⎞ 12 ⎛ r0 ⎞ ⎤
6

U ( r ) = ε ⎢⎜ ⎟ − 2 ⎜ ⎟ ⎥
⎝ ⎠ ⎝ ⎠
Energy

⎣ r r ⎦
r0
Note: Historically, r12 term was chosen
ε Attractive for computational convenience;
other forms are sometimes used

Separation (r) 16
A typical molecular mechanics force field
∑ kb ( b − b0 )
2
U= Bond lengths (“Stretch”)
bonds
2
+ ∑ kθ (θ − θ 0 ) Bond angles (“Bend”) Bonded
angles terms
+ ∑ ∑k ⎡1+ cos ( nφ − φn ) ⎤ Torsional/dihedral angles
φ ,n ⎣ ⎦
torsions n

qi q j
+ ∑∑ Electrostatic
i j >i rij
Non-
Aij Bij bonded
+ ∑∑ − Van der Waals terms
12 6
i j >i r
ij rij
 How are the parameters fit?

• Combination of:
– Quantum mechanical calculations
– Experimental data
• For example: b0 can be estimated from x-ray crystallography,
and Kb from spectroscopy (infrared absorption)
U (b) = K b ( b − b0 )
2

• The torsional parameters are usually fit last. They

absorb the “slop.” Fidelity to physics is debatable.
• These force fields are approximations!
What does the energy function tell us
about protein conformation?
What does the energy function tell us
about protein conformation?

The Boltzmann distribution

 Relating energy to probability

• Given the potential energy associated with a

particular arrangement of atoms (set of atom
positions), what is the probability that we’ll see
that arrangement of atoms?
• Assumptions:
– System is at constant temperature. Atoms are
constantly jiggling around.
– We watch the system for a really long time (allowing it
to fully equilibrate).
 The Boltzmann Distribution
• The Boltzmann distribution relates potential energy to
probability




 p(x) ∝ exp ⎜
( )
⎛ −U x ⎞
⎝ k T ⎟⎠

 B


where T is temperature and kB is the Boltzmann constant

Probability, p(x)
Energy, U(x)

Position (x) Position (x)

 The Boltzmann Distribution
• Key properties:
– Higher energy gives lower probability
– Exponential relationship: each time probability halves, energy
increases by a constant
– Temperature dependence: at higher temperature, need to
increase energy more for same probability reduction





p(x) ∝ exp ⎜
⎛ −U x ( ) ⎞

 ⎝ k BT ⎟⎠

Probability, p(x)
Energy, U(x)

Position (x) Position (x)

What does the energy function tell us
about protein conformation?

Microstates and macrostates

 Protein structure: what we care about
• We don’t really care about the probability that all
the atoms of the protein and all the surrounding
water atoms will be in one precise configuration
• Instead, we care about the probability that protein
atoms will be in some approximate arrangement,
with any arrangement of surrounding water
 Protein structure: what we care about
• In other words, we wish to compare different sets
(neighborhoods) of atomic arrangements
• We define each of these sets as a macrostate 

(A, C). Each macrostate includes many
microstates, or specific atom arrangements x.
– Macrostates—also called conformational states—
correspond to wells in the energy landscape

Probability, p(x)
Energy, U(x)

A A
C

Position (x) Position (x)

 Probabilities of macro states
• Which has greater probability, A or C?
– C is a deeper well, so the individual atomic
arrangements within it are more likely
– A is a broader well, so it includes more distinct
individual arrangements

Probability, p(x)
Energy, U(x)

A A
C

Position (x) Position (x)

 Probabilities of macro states
• Which has greater probability, A or C?
• To get probability of macrostate, sum/integrate over all
microstates within it
⎛ −U ( x ) ⎞
P ( A) = ∫ P(x) ∝ ∫x∈A ⎜⎝
exp ⎟
k BT ⎠ dx
x∈A

• At low temperature, P(C) > P(A)

• At high temperature, P(A) > P(C)

Probability, p(x)
Energy, U(x)

A A
C

Position (x) Position (x)

What does the energy function tell us
about protein conformation?

Free energy
 Free energy of a macrostate

• So far we have assigned energies only to

microstates, but it’s useful to assign them to
macrostates as well.
• Define the free energy GA of a macrostate A such

( )
that:
−GA
P(A) = exp kBT

• This is analogous to Boltzmann distribution formula:

⎛ −U ( x ) ⎞
p(x) ∝ exp ⎜ kBT ⎟⎠
⎝
 Free energy of a macro state
• Define the free energy GA of a macrostate A such
that:
P(A) = exp
−GA
kBT ( )
• Solving for GA gives:
GA = −k BT log e ( P(A))

• One can also express free energy in terms of

enthalpy (mean potential energy, H) and entropy
(“disorder”, S):
GA = H A − TSA You’re not responsible for this last equation,
or for the definitions of enthalpy and entropy
 So which conformational state will a
protein adopt?
• The one with the minimum free energy
– Wide, shallow wells often win out over narrow, deep
ones
• This depends on temperature
• At room or body temperature, the conformational
state (macrostate) of minimum free energy is
usually very different from the microstate with
minimum potential energy