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- Acid-Base Titration Lab
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Protein Structure by NMR:

• Protein structures are calculated by augmenting traditional modeling functions with

experimental NMR data

Molecular Modeling/Molecular Mechanics is a method to calculate the structure and energy of

molecules based on nuclear motions.

• electrons are not considered explicitly

• will find optimum distribution once position of nuclei are known

• Born-Oppenheimer approximation of Shrödinger equation

nuclei are heavier and move slower than electrons

connected with springs, where the weights represent the nuclei

and the springs represent the bonds.

Introduction to Molecular Modeling Techniques

Force Field used to calculate the energy and geometry of a molecule.

• Collection of atom types (to define the atoms in a molecule), parameters (for bond lengths,

bond angles, etc.) and equations (to calculate the energy of a molecule)

• In a force field, a given element may have several atom types.

For example, phenylalanine contains both sp3-hybridized carbons and aromatic carbons.

C-C bond in the ethyl group differs from a C-C bond in the phenyl ring

C-C bond between the phenyl ring and the ethyl group differs from all other C-C

force field contains parameters for these different types of bonds.

Introduction to Molecular Modeling Techniques

• Total energy of a molecule is divided into several parts called force potentials, or potential

energy equations.

• Force potentials are calculated independently, and summed to give the total energy of the

molecule.

Examples of force potentials are the equations for the energies associated with bond

stretching, bond bending, torsional strain and van der Waals interactions.

These equations define the potential energy surface of a molecule.

Introduction to Molecular Modeling Techniques

Potential Energy Equation (Bonds Length)

• Whenever a bond is compressed or stretched the energy goes up.

• The energy potential for bond stretching and compressing is described by an equation

similar to Hooke's law for a spring.

• Sum over two atoms

kl – force constant what we have been discussing up to this point

l – actual/observed bond length

From the structure

Plot of Potential

Energy Function

for Bond Length

Introduction to Molecular Modeling Techniques

Potential Energy Equation (Angles)

• As the bond angle is bent from the norm, the energy goes up.

• Sum over three atoms

what we have been discussing up to this point

kφ – force constant

φ – actual/observed bond angle From the structure

Plot of Potential

Energy Function

for Bond Angle

Introduction to Molecular Modeling Techniques

Potential Energy Equation (Improper Dihedrals)

• As the improper dihedral is bent from the norm, the energy goes up.

• Sum over four atoms

dihedrals in the structure

kω – force constant

ω – actual/observed improper dihedral

Plot of Potential

Energy Function

for Improper

Dihedrals (ω o = 0)

Introduction to Molecular Modeling Techniques

Potential Energy Equation (Dihedral Angles)

• As the dihedral angle is bent from the norm, the energy goes up.

• The torsion potential is a Fourier series that accounts for all 1-4 through-bond

relationships

• Sum over four atoms

dihedrals in the structure

… Fourier Series

An – force constant for each Fourier term Plot of Potential

φ – actual/observed improper dihedral Energy Function

n – multiplicity (same parameter seen in the XPLOR constraint file) for Dihedrals

Multiple minima

Introduction to Molecular Modeling Techniques

Potential Energy Equation (Dihedral Angles)

• Need to include higher terms non-symmetric bonds

Distinguish trans, gauche conformations

torsion angles are energetically equivalent

and should yield 0 torsion energy

Introduction to Molecular Modeling Techniques

Potential Energy Equation (Nonbonded interactions)

• van der waals interaction

Act only at very short distances

atoms ~r6

When atoms get too close, valence shell start to overlap and

repel ~r12

Than becomes

repulsive

Interaction first

attractive

Introduction to Molecular Modeling Techniques

• electrostatic interaction

Electrostatic interaction of charged atoms

Long-range forces

Coulomb’s Law

Coulomb’s Law

Negative interaction if of inversely increases

the same charge distance

Introduction to Molecular Modeling Techniques

Potential Energy Equation (Nonbonded interactions)

• electrostatic interaction

Problem defining dielectric constant (ε)

ε

protein ~ 2-4

ε

solvent ~80

For protein calculations using NMR constraints, typically

How to properly define solvent, buffers, salts, etc?

of calculations.

With electrostatics off during the structure

after the fact to determine the quality of the NMR

structure

Introduction to Molecular Modeling Techniques

Potential Energy Equation (Nonbonded interactions)

• electrostatic interaction

Problem defining dielectric constant (ε)

1) Don’t use electrostatic potential energy during structure

calculation

2) Use a single dielectric constant

εprotein ~ 2-4; εsolvent ~80

Use explicit solvent in structure calculation

Improved structure quality

Increased computational time

Properly defining solvent

Properly defining force fields

behavior in solvent

Introduction to Molecular Modeling Techniques

Why Is the Potential Energy Function Not Sufficient to Fold A Protein?

• It is Not A complete function

primarily short-range geometry with many equal solutions

VDW and electrostatics only contribute over short distances

How do you bring distant regions of the primary chain into contact?

3N where N is the number of amino acids

hydrophobic interactions, hydrogen-bond formation, secondary structure interactions (helix

How do you define a mathematical equation defining these contributions?

Energy Function,

improving the parameters

and defining alternative

ab inito methods of

folding a protein are

major areas of Molecular

Modeling research.

Introduction to Molecular Modeling Techniques

Potential Energy Equation (NMR Constraints)

• hydrogen bond constraint

based on an empirical formula derived from high quality X-ray structures in the PDB

violation energy is based on deviations from expected h-bond length (R) and angle (φ)

(relationship between R and φ)

Nrestra int s

EHB = kHB ∑ (1

m =1

/ R 3

− A − [ B /{2 . 07 + cos φ 3 2

NHO} ])

Introduction to Molecular Modeling Techniques

For a Given Set of Atomic Coordinates, An Energy for the Structure Can Be

Calculated Based on the Set of Potential Energy Functions

ETOTAL = Echem + wexpEexp

Eexp = ENOE + Etorsion + EH-bond + Egyr + Erama + ERDC + ECSA + Epara

Echem = Ebond + Eangle + Edihedral + Evdw + Eelectr

What Relationship Does This Energy Value Have to Any Experimental Observation?

NOTHING!

The energy value simply indicates how well the structure conforms to the expected parameters.

It does not indicate the stability of the protein (∆G).

Calculating a ∆E between the protein with/without a ligand does not indicate the binding

affinity of the ligand or the induced stability of the complex

Introduction to Molecular Modeling Techniques

What Relationship Is There Between the Force Constants and Experimental

Observations?

come from IR, raman spectroscopy and ab inito calculations.

determined by “trial & error” or empirically to

obtain a proper balance and weighted

contribution of each experimental parameter to

the calculated structure.

Introduction to Molecular Modeling Techniques

What Do We Mean By a Proper Balance?

H

H-H distance constraint of 3.0 Å with 25 kcal/mol force C C

(ceiling of 100 kcal/mol)

Distance constraint is violated (properly)

with no distortion in bond lengths

H H

H-H distance constraint of 3.0 Å with 500 kcal/mol force

C C

Want to Keep All Known Geometric Values Distance constraint is satisfied (improperly)

Within Proper Ranges with large distortion in bond lengths

Introduction to Molecular Modeling Techniques

Eexp = ENOE + Etorsion + EH-bond + Egyr + Erama + ERDC + ECSA + Epara

Echem = Ebond + Eangle + Edihedral + Evdw + Eelectr

Molecular Minimization starting from some structure (R), find its potential energy using the

potential energy function given above. The coordinate vector R is then varied using an optimization

procedure so as to minimize the potential energy ETOTAL(R).

second law of motion is solved to find how the position for each atom of the system varies with

time. To find the forces on each atom, the derivative vector (or gradient) of the potential energy

function given above is calculated. Factors such as the temperature and pressure of the system

can be included in the treatment.

Introduction to Molecular Modeling Techniques

Anfinsen's Thermodynamic Hypothesis

The native conformation of a protein is the conformation with the lowest free energy (∆G)

global minimum of the free energy surface.

Rather difficult (and expensive) to calculate free energies

denatured ribonuclease A (124

amino acids, 4 disulphides)

produced in 8 M urea and reducing

agent (β -mercaptoethanol) could be

re-activated by dialysing out the

denaturant in oxidizing conditions

Introduction to Molecular Modeling Techniques

Levinthal Paradox

If the entire folding process was a random search, it would require too much time

Initial stages of folding must be nearly random.

Conformational changes occur on a time scale of 10-13 seconds.

if each residue has only 3 possible conformations (far less than reality)

Even if a significant number of these conformations are sterically disallowed, the folding

Energy barriers probably cause the protein to fold along a definite pathway

Introduction to Molecular Modeling Techniques

Molecular Minimization

• moves the Cartesian coordinates (X,Y,Z position) for each atom to obtain minimal energy

Eexp = ENOE + Etorsion + EH-bond + Egyr + Erama + ERDC + ECSA + Epara

Echem = Ebond + Eangle + Edihedral + Evdw + Eelectr

• result is dependent on the starting structure

• finds local not global minima

• typically, only small movements in atom position are made

starting structure looks similar to ending structure

large changes may occur for significantly distorted structures (stretch bonds)

could invert chirality

Introduction to Molecular Modeling Techniques

Molecular Minimization

• minimization will fail for severely distorted structures

a poorly docked ligand onto a protein where bonds or atoms are overlapped

would minimize since the Cδ of the

Leu side-chain penetrates the center

of the benzene ring

In order to properly refine this poor structure, the minimization protocol would need to pull

the Cδ back through the ring which would require first going to a higher energy structure.

This will not occur since the trend for minimization is to move towards a lower energy.

The “minimized” structure will probably result with a stretched and distorted Cδ-Cγ

bond as it moves the Cδ away from the ring from the other direction

the benzene ring and the remainder of the Leu side-chain will also be distorted in an

Introduction to Molecular Modeling Techniques

peaks and valleys.

moves “down hill”.

structural landscape

intermediate structures to get to a

lower minima.

Introduction to Molecular Modeling Techniques

leads to the global minimum at the base of the funnel.

Introduction to Molecular Modeling Techniques

Molecular Minimization

• Process Overview

The molecular potential U depends on two types of variables:

is zero:

or

Where xi denote atomic Cartesian coordinates and N is the number

of atoms

matrix is positive definite, i.e. for any 3N-dimensional vector u:

eigenvalues of F are positive at a minimum. The second derivative

matrix is denoted by F in molecular mechanics and H in mathematics,

and is defined as:

One measure of the distance from a stationary point is the rms gradient:

Introduction to Molecular Modeling Techniques

Molecular Minimization

• Process Overview

minima occurs when the first derivative is zero and when the second derivative is positive.

molecular energy minimization is often performed in a series of steps

the coordinates at step n+1 are determined from coordinates at previous step n

the initial step is a guess

a systematic or random search is not practical (Levinthal Paradox)

search step (δ ) is performed in the direction of fastest decrease of U,

n

opposite of the gradient g

length of the step.

structures

may be very slow near a solution

Introduction to Molecular Modeling Techniques

Molecular Minimization

• Process Overview

• Conjugate Gradient (Powell)

modify steepest descent to increase efficiency

current step vector is not similar to previous step vectors

accumulates information about the energy function from one iteration to the next

minimization calculations is completed:

been calculated.

• a predefined value of the gradient (g)

has been reached. (gradient very

rarely actually reaches exactly zero)

Introduction to Molecular Modeling Techniques

Molecular Dynamics (MD)

• moves the Cartesian coordinates (X,Y,Z position) for each atom by integrating their equations of

motion

change in position with time gives velocity

follow the laws of classical mechanics, most notably Newton's Second law:

The force on atom i can be computed directly from the derivative of the potential energy

function (U) with respect to the coordinates ri, Fi = -δU/δri.

to initiate MD we need to assign initial velocities

This is done using a random number generator using the constraint of the Maxwell-

Boltzmann distribution.

where:

Hamiltonian H(Γ) where Γ represents the set of positions and momenta

Target Temperature (T)

Boltzman constant (kB)

Introduction to Molecular Modeling Techniques

Molecular Dynamics (MD)

The temperature is defined by the average kinetic energy of the system according to the

kinetic theory of gases.

– internal energy of the system is U = 3/2 NkT

– kinetic energy is U = 1/2 Nmv2

where :

N is the number of atoms

v is the velocity

m is the mass

T is the temperature

k is the Boltzman constant

By averaging over the velocities of all of the atoms in the system the temperature can

be estimated.

Maxwell-Boltzmann velocity distribution will be maintained throughout the

simulation.

• If system has been energy minimized potential energy is zero and temperature is zero

• Need to “heat” system up to desired temperature

scale velocities: v = (3kT/m)1/2

• Calculate a trajectory in a 6N-dimensional phase space (3N positions and 3N momenta)

measure trajectories in small time steps, usually 1 femto-second (fs)

Energy Only (Univariate)

Method

• Simplest to implement

• Proceeds one

direction until energy

increases, then turns

90º, etc.

• Least efficient

– many steps

– steps are not guided

• Not used very much.

Steepest Descent Method

• Simplest method in use

• Follows most negative

gradient (max. force)

• Fastest method from a

poor starting geometry

• Converges slowly near

the energy minimum

• Can skip back and forth

across a minimum.

Conjugate Gradient Method

• Adds ‘history’ to simplicity

of steepest descent

method to implicitly

gather 2nd derivative

information to

guide the search.

• Variations on this

procedure are the

Fletcher-Reeves, the

Davidon- Fletcher-Powell

and the Polak-Ribiere

Second Derivative Methods

• The 2nd derivative of the

energy with respect to

X,Y,Z [the Hessian]

determines the pathway.

• Computationally more

involved, but generally

fast and reliable, esp.

near the minimum.

• Quasi-Newton, Newton-Raphson,

block diagonal Newton-Raphson

Approaches to Locating the

Global Minimum Energy

•

Structure

Dihedral driving (systematic)

• Randomization-minimization (Monte Carlo)

• Molecular dynamics (Newton’s laws of motion)

• Simulated Annealing (reduce T during MD run)

• Genetic Algorithms (start with a population of

conformations; modify slightly; retain lowest

energy ones, repeat)

• Trial & error (poor)

Methods are tedious, but absolutely necessary

if the result is to be meaningful!

Caveats about Minimum

Energy Structures

• What does the global minimum energy

structure really mean?

• Does reaction/interaction of interest

necessarily occur via the lowest energy

conformation?

• What other low energy conformations are

available? (Boltzmann distribution/ensemble

of conformations and probability/entropy

considerations may be important).

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