Curso de Genómica Funcional y Bioinformática (IBI514)

An introduction to Molecular
Dynamics simulations (MDs)
References

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Why we do simulation:
In some cases, experiment is:

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What is it good for?
The essence of molecular simulations resides in the connection between the macroscopic world and the
microscopic world provided by the theory of statistical mechanics.
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*
, complejo
Macroscopic properties are often determined by molecule-level behavior.

Quantitative and/or qualitative information about macroscopic behavior of macromolecules can be obtained
from simulation of a system at atomistic level.

The idea is mimic what atoms do in real life, assuming a given potential energy function.

MDs calculate the motion of the atoms in a molecular assembly using Newtonian dynamics to determine the
net force and acceleration experienced by each atom. Each atom i at position ri is treated as a point with a
mass mi and a fixed charge qi.
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MDs: Verlet Method

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Newton’s equation represents a set of N second order differential equations which are solved numerically at
discrete time steps to determine the trajectory of each atom.
Deriving the Verlet algorithm

Uses positions and accelerations at time t and the positions from time t-δt to calculate new positions at time
t+δt.
What is a Force Field?
Energio
del Sistema
Encomo resorte

HOOKE
In MDs, a molecule is described as a series of Ley
charged spheres (atoms) linked by springs (bonds).

Campo de FD
-> MDs la Molecul
es serie de esferos
cargados(atomos)
anidas X resorte
cencoces)
.
(by Hooke
Evolucion temporal
Conside Enloayintercon
evaals
tosion
La sin union
electrostatico entra atomos

campos Fr

Campof ; Emacions
,
constants
paro reproduci geometra

decularypropiedeastructura a
probados .

To describe the time evolution of bond lengths, bond angles and torsions, also the non-bonding van der Waals
and electrostatic interactions between atoms, force-fields are used.

The force-field is a collection of equations and associated constants designed to reproduce molecular geometry
and selected properties of tested structures.
 Kinetic and potential energies:

Total energy (potential + kinetic) should be conserved:

• In atomic arrangements with lower potential energy, atoms

move faster.

• In practice, total energy tends to grow slowly with time

due to numerical errors (rounding errors).

• In many simulations, one adds a mechanism to keep the

temperature roughly constant (a “thermostat”)
Kinetic energy (Ek):
Potential energy (EU) terms and functions in a Force Field

Bond interactions

+ -
Non-bond interactions
vd electrostatic
W

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 Eve distancia
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 Solvent is important:
Ignoring the solvent (the molecules surrounding the molecule of interest) leads to major artifacts:

– Water, salt ions (e.g., sodium, chloride), lipids of the cell membrane.

Two options for taking solvent into account:

– Explicitly represent solvent molecules

• High computational expense but more accurate.
• Usually assume periodic boundary conditions (a water
molecule that goes off the left side of the simulation box
will come back in the right side, like in PacMan).

– Implicit solvent:
• Mathematical model to approximate average effects of
solvent.
• Less accurate but faster.

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Solvation effects:

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 A condicions limits
Explicito
-

La Region interes esfero 1A

Explicit solvation:
os
.

* Malecios H2O -D
compo
+

↓
-

Restora Apaience T
-

->

al central
en esfroHLO a gravel
-
Solvatodo EstoCAStiCAS
Simulado en

entano-prepeticon
de stoadirectors
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PERODICAS

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Implicit solvation: iMPliCto
- D constante
N : 4, 8
Deteccion : Funcon
Efecto
de
deteccion
distonca
min
del
disolvente
.
atomo

- Modelo solvente
impocito :
Poison (PB)
-> Born Generalizado
OB

EH en robalo H2O
Se pierden

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Introduction to molecular surfaces:

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Time scales of relevant biological events

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 1 fs as a time barrier
Dynamics simulations are limited by the highest frequency vibration.

Ideally the timestep should be 1/10 highest frequency.

In most cases C-H bond stretching (10-14 s) is the fastest mode.

So, divide time into discrete time steps, no more than a few femtoseconds (10-15 s) each.

At each time step:

- Compute the forces acting on each atom, using a molecular mechanics force-field.
- Move the atoms a little bit, update position and velocity of each atom using Newton’s laws of
motion.

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 PQ MDs es
computationalmente

Why is MD so computationally intensive?

-> Muchos pasos en(t)
intensivo
?? Dominado
No unidas
.
X

PQ
interaccions
actuan par de
atomos en sistema de Natomos

NoHemiNOS NO ENHAN
The

Ignorar inters cons mes

Se puede
mes d
alla de atomos separados x

Many time steps (millions to trillions) 1 distonca de Corte

-DVAWaals
la
si

distancia
,
fijo ??
con vapidamente
con .

-> Electrostatico NO
. CEN unto

con la distance

Substantial amount of computation at every time step:

– Dominated by non-bonded interactions, as these act between every pair of atoms. In a system of N
atoms, the number of non-bonded terms is proportional to N2

– Can we ignore interactions beyond atoms separated by more than some fixed cutoff distance?
– For van der Waals interactions, yes. These forces fall off quickly with distance.
– For electrostatics, no. These forces fall off slowly with distance.

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Determining where drug molecules bind, and how they exert their effects:
We used simulations to determine where this molecule binds to its receptor, and how it changes the binding
strength of molecules that bind elsewhere (in part by changing the protein’s structure).

Determinar donde se unes

Moleculos de Formaco

y como geran efetos

↳ la mole
MAs para
ver dende
Seune receptor como
a su y
cambia la FP de unior.

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2
 Pasos Paro tip .
co MDs
Preparor Sistema

Steps in a typical MDs Topologia

Minimization
La Reconciar
y Parametros

la estructuro con campo

Utilizado
colefaccion - ↑ i de sis temo
Sis estable
Equilibrio a

1. System preparation Dinamico -a simular

descodes
.
condicions

dotor

– topology and parameters. Analisis - Recopicor

Evamor propieddes Macro
a
Experts
· toconarcon

2. Minimization
– Reconcile observed structure with force-field used.

3. Heating
– Raise temperature of the system.

4. Equilibration
– Ensure system is stable.

5. Dynamics
– Simulate under desired conditions (NVE, NpT, etc).

6. Analysis
– Collect your data
– Evaluate observables (macroscopic level properties)
– Or relate to single molecule experiments.
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 System preparation:

Topology:

• atom types are assigned to identify different elements and different molecular
orbital environments.
• charges are assigned to each atom.
• connectivities between atoms are established.

Parameters:

• force constants necessary to describe the bond energy, angle energy, torsion
energy, nonbonded interactions (van der Waals and electrostatics).
• suggested parameters for setting up the simulation (T, P, simulation time,
etc).

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 Minimization:

The energy of the system can be calculated using the force-field. The
conformation of the system can be altered to find lower energy
conformations through a process called minimization.

Minimization algorithms:
• Steepest descent (slowly converging – use for highly restrained
systems.
• Conjugate gradient (efficient, uses intelligent choices of search
direction – use for large systems).
• Newton-Raphson (calculates both slope of energy and rate of
change).

https://www.youtube.com/watch?v=OMTVVFQGV8Y

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 Molecular Dynamics Ensembles

• Constant energy, constant volume and constant number of particles (NVE)

• Constant temperature, constant volume and constant number of particles (NVT)

• Constant temperature, constant pressure and constant number of particles (NPT)

Choose the ensemble that best fits your system.

https://www.youtube.com/watch?v=xcMSHy3CqXA
https://www.youtube.com/watch?v=gFcp2Xpd29I
https://www.youtube.com/watch?v=GlLHYIFeHvQ

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Limitations of MDs: timescales
Simulations require short time steps for numerical stability (1 time step ≈ 2 fs (2×10–15 s))

Structural changes in proteins can take microseconds (10–6 s), milliseconds (10–3 s), or longer

Until recently, simulations of microseconds were rare.

Advances in computer power have enabled microsecond simulations, but simulation timescales remain a
challenge.
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Enabling longer-timescale simulations is an active research area, involving:
– Algorithmic improvements
– Parallel computing
– Hardware: GPUs, specialized hardware

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Limitations of MDs: Covalent bonds cannot break or form during (standard) MDs.

All the covalent bonds in a system will not break or form during the simulation.

including:
– disulfide bonds between cysteines
– acidic or basic amino acid residues can lose or gain a hydrogen (i.e., a proton).

MDs is not reactive.

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MDs Results: an overview to TASK-2 K2P channel

3
 T2Tre2OO T2Tre1CC

T2Tre2OO-K245+ T2Tre2OO-K2450 T2Tre1CC-K245+ T2Tre1CC-K2450

3
Root Mean Square Deviation
(RMSD):

3
Root Mean Square Fluctuation (RMSF):

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The dimensions of the fenestrations during
the simulation:

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The orientation of K245 clustered

T2Tre2OO-K245+ T2Tre1CC-K245+

72% 76%
64% 68%
28% 24%
36%

32%

T2Tre2OO-K2450 T2Tre1CC-K2450

71% 82%
67% 76%
33% 18%
24%
29%

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Computational pKa prediction:

water reorientation dielectric of protein

protein reorganization = electrostatic interactions (protein-protein, protein-water)
water penetration solvation effect

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The lipids protruding toward the fenestrations and the central cavity:

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The water molecules protruding toward the fenestrations and the central cavity.

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Electrostatic potential difference (∆Φ) of K245 in TASK-2 systems

ΔФ = ФTASK-2 [K245+] – ФTASK-2 [K2450]

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Potential of mean force (PMF) of K245 in TASK-2 systems

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Secondary structure throughout the simulation:

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Secondary structure throughout the simulation:

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Intermolecular interactions:

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Intermolecular interactions:

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Ligand analysis:

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Ligand analysis:

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Ligand analysis:

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Ligand analysis:

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