C7790 Introduction to Molecular Modelling -1C7790
Introduction to Molecular
Modelling
TSM Modelling Molecular Structures
Petr Kulhánek
kulhanek@chemi.muni.cz
National Centre for Biomolecular Research, Faculty of Science
Masaryk University, Kamenice 5, CZ-62500 Brno
PS/2020 Distant Form of Teaching: Rev1
Lesson 15
Potential Energy Surface III
C7790 Introduction to Molecular Modelling -2Local
vs global minimum on PES
E(x)
x
configurations
local minima
global minima
REMEMBER: This is 1D projection of E(R), which is a function
of 3N variables (N-number of atoms).
To find a global minimum, it is necessary to find ALL local minima. Due to PES
complexity, this is not computationally achievable even for small systems.
C7790 Introduction to Molecular Modelling -3Local
vs global minimum on PES
E(x)
x
configurations
local minima representing some
conformational changes
nearest "global" minimum
for example
reactant state
global minimum representing a given state
for example
product state
REMEMBER: This is 1D projection of E(R),
which is a function of 3N
variables (N-number of
atoms).
C7790 Introduction to Molecular Modelling -4Local
vs global minimum on PES
Finding local minimum:
➢ it is rather simple task, which employs local geometry optimizers
➢ the success of finding of local minimum is almost always guaranteed (problematic
might by shallow minima).
Finding global minimum:
➢ it is VERY difficult task, which can employ deterministic and/or stochastic methods
such as
➢ genetic algorithms
➢ Monte-Carlo sampling algorithms
➢ parallel tempering
➢ others
➢ the success of finding of global minimum is not guaranteed
C7790 Introduction to Molecular Modelling -5Finding
the optimal
geometry (local minima)
C7790 Introduction to Molecular Modelling -6Optimal
geometry
local minima
C7790 Introduction to Molecular Modelling -7Optimization
methods
Geometry optimization methods
I. zero order (energy only)
▪ downhill simplex method
II. first order (energy and gradient only)
▪ steepest descent method
▪ conjugate gradient method
III. second order (energy, gradient and Hessian)
▪ Newton's method
IV.pseudo-second order (energy, gradient and approximate Hessian)
▪ Broyden-Fletcher-Goldfarb-Shanno method (BFGS)
)(RE
Task: find R such E(R) is minimum (has zero gradient)
min!
the most often used approach
C7790 Introduction to Molecular Modelling -8Optimization
methods
Geometry optimization methods
I. zero order (energy only)
▪ downhill simplex method
II. first order (energy and gradient only)
▪ steepest descent method
▪ conjugate gradient method
III. second order (energy, gradient and Hessian)
▪ Newton's method
IV.pseudo-second order (energy, gradient and approximate Hessian)
▪ Broyden-Fletcher-Goldfarb-Shanno method (BFGS)
Above mentioned methods (algorithms) are general for any function:
The function f is called, variously, an objective function, a loss function or cost function
(minimization), a utility function or fitness function (maximization), or, in certain fields,
an energy function or energy functional. A feasible solution that minimizes (or
maximizes, if that is the goal) the objective function is called an optimal solution.
https://en.wikipedia.org/wiki/Mathematical_optimization
C7790 Introduction to Molecular Modelling -9Zero-order
methods
Downhill simplex method
(Nelder-Mead algorithm)
➢ iterative method
➢ only energy is required (no gradient or Hessian)
➢ can escape local minima and can find nearest
"global" minimum
https://sudonull.com/post/69185-Nelder-Mead-optimization-method-Python-implementation-example
https://codesachin.wordpress.com/2016/01/16/nelder-mead-optimization/
Other zero-order methods:
➢ BOBYQA
➢ COBYLA
➢ majority of global optimizers
➢ etc.
Further details:
https://en.wikipedia.org/wiki/Derivative-free_optimization
C7790 Introduction to Molecular Modelling -10First-order
methods
https://en.wikipedia.org/wiki/Gradient_descent
Steepest Descent Method
➢ iterative method
➢ only gradient is required (energy is only
required for monitoring)
➢ it can find a local minimum
𝑹 𝑛= 𝑹 𝑛−1 − 𝛾
𝜕𝐸(𝑹 𝑛−1)
𝜕𝑹
energy gradient"step" size
Other first-order methods:
➢ conjugate-gradients
➢ etc.
step size can be a constant, varying, or different for geometry domains (bonds, angles, …)
➢ Rarely used for QM as these methods require
more iterations to reach a minimum than psedosecond
order methods.
➢ Quite often used for MM.
C7790 Introduction to Molecular Modelling -11Second-order
methods
𝑹 𝑛= 𝑹 𝑛−1 − 𝛾
𝜕2 𝐸(𝑹 𝑛−1)
𝜕𝑹2
−1
𝜕𝐸(𝑹 𝑛−1)
𝜕𝑹
Newton's Method
➢ iterative method
➢ gradient and Hessian are required (energy is only required for monitoring)
➢ it can find a local minimum
➢ the method converges significantly faster (in smaller number of steps) than zeroorder
or first-order methods
➢ it is EXTREMELY computationally expensive due to Hessian calculations
energy gradient
"step" size Hessian
Solution: pseudo-second order methods (such as BFGS)
➢ initial Hessian is approximated (empirical approaches, or unit matrix)
➢ in next iterations, Hessian is updated using gradients
➢ Hessian is thus improving during optimization, which results in faster
convergence in final steps
https://en.wikipedia.org/wiki/Newton%27s_method_in_optimization
step size can be a constant, varying, or different for geometry domains (bonds, angles, …)
C7790 Introduction to Molecular Modelling -12Cartesian
vs Internal Coordinates
O
H 1 0.974298
O 1 1.454349 2 96.868054
H 3 0.974298 1 96.868054 2 239.552651
Cartesian coordinates
Internal coordinates (Z-matrix)
bond length bond angle torsion angle
3N
3N-6
3N-5
Number of degrees of freedom:
Number of degrees of freedom:
(linear diatomic molecule)
x y z
O -0.180077 -0.046023 -0.062789
H 0.196208 -0.747659 0.498793
O 0.006537 1.047922 0.877207
H -0.931885 1.299156 0.951390
O
O
H
H
C7790 Introduction to Molecular Modelling -13Internal
vs Cartesian coordinates
Optimization in internal coordinates converges fasters than in Cartesian coordinates:
➢ Hessian in internal coordinates can naturally provide difference between force
constants of different geometry parameters (bonds, angles, torsions)
➢ This property of internal coordinates allows to use different step sizes for different
geometry parameters (bonds, angles, torsions).
In some rare cases, optimization in internal coordinates can fail (oscillation, etc.)
Potential solutions:
➢ use different optimization algorithm
➢ switch to Cartesian coordinates
C7790 Introduction to Molecular Modelling -14Practical
realizations
Avogadro employing MM potential
Nemesis employing MM potential
Gaussian employing QM potential
# RHF/cc-pVDZ Opt NoSymm
C7790 Introduction to Molecular Modelling -15Optimization
of initial model
E(x)
x
configurations
for example
reactant state
for example
product state
REMEMBER: This is 1D projection of E(R),
which is a function of 3N
variables (N-number of atoms).starting (built)
models
OK
but not global minima
Models derived from high resolution X-ray structures are
not problematic.
C7790 Introduction to Molecular Modelling -16Optimization
of initial model
E(x)
x
configurations
for example
reactant state
for example
product state
starting (built)
model
BAD
REMEMBER: This is 1D projection of E(R),
which is a function of 3N
variables (N-number of atoms).
➢ In silico (built) models are very susceptible to initial structure.
➢ Therefore, frequency (vibration, Hessian) analysis is a MUST to check
the nature of optimized stationary point.
C7790 Introduction to Molecular Modelling -17-
Summary
➢ It is relatively easy to find a local minimum.
➢ All geometry optimizers stops at a stationary point (a point with zero gradient), which
dos not necessarily need to represent a local minimum.
➢ Due to complexity of PES, it is important to verify a nature of found stationary point
because the found geometry can represent a transition state or a higher order saddle
point.
➢ This is especially important for in silico models, which usually starts a far away from
optimal geometry.
C7790 Introduction to Molecular Modelling -18-
Homework
C7790 Introduction to Molecular Modelling -19Numerical
gradient calculation
Forward differences Central differences
x0x-1 x1x0 x1
h
xEhxE
xx
xExE
x
E
x
)()()()()( 00
01
01
0
−+
=
−
−
=

 R
h
hxEhxE
xx
xExE
x
E
x 2
)()()()()( 00
11
11
0
−−+
=
−
−
=


−
−R
C7790 Introduction to Molecular Modelling -20Numerical
gradient calculation
Forward differences Central differences
x0x-1 x1x0 x1
h
xEhxE
xx
xExE
x
E
x
)()()()()( 00
01
01
0
−+
=
−
−
=

 R
h
hxEhxE
xx
xExE
x
E
x 2
)()()()()( 00
11
11
0
−−+
=
−
−
=


−
−R
it is calculated onceit is calculated for each
gradient component
a total of 3N + 1 energy calculations
they are calculated for
each gradient component
a total of 6N energy calculations
C7790 Introduction to Molecular Modelling -21Tasks
I
1. Express the gradient of the function E(R) according to the Cartesian
coordinates of both atoms.
2. The system contains 300 atoms. The calculation of its energy by the quantumchemical
method takes 15 minutes. Calculation of energy and analytical
gradient then 20 minutes.
1. Determine the calculation time of the numerical gradient and compare
it with the calculation time of the analytical gradient.
2. Determine the calculation time of numerical Hessian, which is
calculated a) from energies and b) from analytical gradients.
3. Suggest a way to speed up the calculation of the numerical gradient a
Hessian.
2
0 )(
2
1
)( rrKE −=R
C7790 Introduction to Molecular Modelling -22-
1) For the function below, determine the character of the points with values:
a) x = 1
b) x = 0
c) x = -1
2) In what situation can the second derivative of a function be zero?
3) What is the relationship between the extent of the reaction x and reaction coordinate rC
(also referred to as x)?
Tasks II
33015)( 2
++= xxxE
C7790 Introduction to Molecular Modelling -23Tasks
III
1. Study the mentioned local geometry optimization methods. Focus on their
principle, advantages and disadvantages compared to other optimization
methods.
Literature:
(1) Leach, A.R. Molecular Modeling: Principles and Applications, 2nd ed .; Prentice Hall:
Harlow, England; New York, 2001.
(2) Jensen, F. Introduction to Computational Chemistry, 2nd ed .; John Wiley &
Sons:Chichester, England; Hoboken, NJ, 2007.