Assignment #01

Subject Title:
Computational Methods for Biological Systems
BCH-631
Submitted To:
Dr. Ghulam Mustafa
Submitted By:
Qamar Shehzad
6137
BS Biochemistry
8th (Morning)
Topic :
Introduction to Molecular Dynamics Simulation

Government College University Faisalabad

Molecular dynamics (MD) simulations, first developed in the late 1970s, seek to overcome this
limitation by using simple approximations based on Newtonian physics to simulate atomic
motions, thus reducing the computational complexity. First, a computer model of the molecular
system is prepared from nuclear magnetic resonance (NMR), crystallographic, or homology-
modeling data. The forces acting on each of the system atoms are then estimated from an
equation. In brief, forces arising from interactions between bonded and non-bonded atoms
contribute. Chemical bonds and atomic angles are modeled using simple virtual springs, and
dihedral angles (that is, rotations about a bond) are modeled using a sinusoidal function that
approximates the energy differences between eclipsed and staggered conformations. Non-bonded
forces arise due to van der Waals interactions, potential and charged (electrostatic) interactions,
modeled using Coulomb's law. While crystallographic studies like these convincingly
demonstrate the important role protein flexibility plays in ligand binding, the expense and
extensive labor required to generate them have led many to seek computational techniques that
can predict protein motions. Unfortunately, the calculations required to describe the absurd
quantum-mechanical motions and chemical reactions of large molecular systems are often too
complex and computationally intensive for even the best supercomputers. The simulation
output, the trajectory, is an ordered list of 3N atom coordinates for each simulation time (or
snapshot).
Abbreviations: Epot, potential energy; t, simulation time; dt, iteration time; For each spatial
coordinate of the N simulated atoms (i): x, atom coordinate; F, forces component; a,
acceleration; m, atom mass; v, velocity (Fig.1).
Figure.1. The simulation output trajectory and coordinate with simulation time.

2. Principle:
We carry out computer simulations in the hope of understanding the properties of assem-
blies of molecules in terms of their structure and the microscopic interactions between
them. This serves as a complement to conventional experiments, enabling us to learn
something new, something that cannot be found out in other ways. The two main families
of simulation technique are molecular dynamics (MD) and Monte Carlo (MC); addition-
ally, there is a whole range of hybrid techniques which combine features from both. In
this lecture we shall concentrate on MD. The obvious advantage of MD over MC is that it
gives a route to dynamical properties of the system: transport coefficients, time-dependent
responses to perturbations, rheological properties and spectra.
Computer simulations act as a bridge (see Fig. 1) between microscopic length and time
scales and the macroscopic world of the laboratory: we provide a guess at the interactions
between molecules, and obtain ‘exact’ predictions of bulk properties. The predictions are
‘exact’ in the sense that they can be made as accurate as we like, subject to the limita-
tions imposed by our computer budget. At the same time, the hidden detail behind bulk
measurements can be revealed. An example is the link between the diffusion coefficient
and velocity autocorrelation function (the former easy to measure experimentally, the latter
much harder). Simulations act as a bridge in another sense: between theory and experi-
ment. We may test a theory by conducting a simulation using the same model. We may
test the model by comparing with experimental results. We may also carry out simulations
on the computer that are difficult or impossible in the laboratory (for example, working at
extremes of temperature or pressure).
Ultimately we may want to make direct comparisons with experimental measurements
made on specific materials, in which case a good model of molecular interactions is essen-
tial. The aim of so-called ab initio molecular dynamics is to reduce the amount of fitting
and guesswork in this process to a minimum. On the other hand, we may be interested
in phenomena of a rather generic nature, or we may simply want to discriminate between
good and bad theories. When it comes to aims of this kind, it is not necessary to have a
perfectly realistic molecular model; one that contains the essential physics may be quite
suitable.

3. Nanoparticles: a studying by MD Simulation:

Nanocrystalline materials have become of wide interest in recent years owing to their
potentially useful properties. One of the challenges in utilizing these new materials is
learning how to assemble controllably the fundamental nanoparticle building blocks. Since
little is known about such assembly, we have begun studies of sintering in these materials.
At the very earliest stages of sintering, the single particles must ®rst interact with each
other or with substrates; consequently we have initiated our investigation with the simple
case of sintering of two Cu nanoparticles. The macroscopic models that are currently
available to treat this type of problem, however, are based on the kinetic,
thermodynamic and mechanical properties of solids which are typical of bulk crystals but
these may be very different in nanoparticles and a more atomistic approach is necessary.
For this study, molecular-dynamics (MD) computer simulations were employed. Although MD
simulations are often not practical for problems such as sintering where diffusion is
involved, it will be demonstrated that for nanoparticle systems sintering reactions can
occur on a time scale of tens of picoseconds. The aim of the present work therefore,
was ® rstly to test the feasibility of using M D sim ulations to study sintering in
nanoparticle systems and secondly to elucidate them mechanisms in the sintering of two
nanoparticles in contact.

4. Applications | Uses:
4.1 Understanding allostery

Most regulation phenomena in proteins are explained within conformational transitions. The
concept of allostery that translates conformational dynamics in functional implications has been
analyzed since the early times of protein biochemistry. Conformation shift involved in allostery
spans from small rearrangements to large quaternary shifts as those originally accounted by the
Monod model. In any case, there is a general agreement that conformational shifts involved in
allosteric transitions are simple in terms of collective movements.For this reason, molecular
simulations could be a natural tool to understand allostery. However, the ability of free atomistic
simulation algorithms to follow a complete transition path is limited. Most of the traditional
reports of simulations in this field use simplified frameworks, like discrete MD or Go-Models,or
even popular nonsimulation equivalents like elastic network models,and seek to find the
transition path between known experimental structures. With full atom representations, it is usual
to trick the algorithm by using targeted, or supervised MD where the simulation is artificially
driven to the desired conformation. In this case, the analysis of the path could give insight into
the energetics and details of the allosteric transition. For those cases where allosteric regulation
is known to occur, but one of the ends is unknown, long simulations (alone or with enhanced
conformational sampling) are required. The direct use of conformational ensembles without any
conditioning is still out of the routine possibilities of present MD simulations; however, specific
cases with well-defined collective motions could be feasible.
 4.2 Molecular docking and drug design
One of the most practical application of the concept of molecular recognition are docking
strategies, either small molecule or protein docking. To understand how a ligand, typically a
substrate or a regulator, binds to its macromolecular counterpart is a key issue in the
understanding of function itself, and it is the basis of structurally driven drug design. The
recognition process is by nature dynamic. Molecules are flexible entities, and the recognition
process itself implies structural rearrangements, and this shape adjustment is part of the binding
process not only from the structural point of view, but also from the energetics. Although this is
a generally well-accepted idea, docking algorithms are far from considering dynamic effects as a
routine. Most docking or virtual screening codes work on rigid structures as obtained from the
PDB. In this experiment, all receptor structures correspond to the same protein, but crystallized
with a different ligand; and all ligands are known to bind the receptor in the same place and pose.
In these conditions, the experiment just measures the impact of small receptor rearrangements
caused by ligand binding, on the docking efficiency.This problem is especially relevant in
protein–protein docking where considerable differences are found between bound and unbound
structures. For ligand-docking methods, ligand flexibility could be largely recovered by using
conformer families.In the case of protein flexibility, solutions are not so extended. Most of them
use algorithms to select from a limited alternative set of protein conformations, either
precomputed or simulated. The concept of “ensemble docking” usually requires the selection of a
representative set of snapshots coming from a simulation and uses them as targets in normal
docking procedures. Integration of docking and simulation in a single calculation is less popular,
but some examples have been reported.
4.3 Refining structure predictions
Structure prediction has been one of the most ancient problems addressed in structural
bioinformatics. MD, including the longest simulations performed, has been extensively used for
ab initio protein structure prediction, aiming to simulate protein folding from scratch, although
this is not the preferred strategy to obtain theoretical model of protein structure. Instead,
template-based modeling is the most efficient technique. In template-based modeling, one or
several 3D structures of protein showing a reasonable degree of similarity to the protein of
interest are taken as templates. Irrespective of the modeling algorithm, the end result is a model
bearing the new amino acid sequence and a structure averaging the used templates. In most
cases, the last step of the prediction procedure implies relaxation of the structure using normally
molecular mechanics. In others, restrained simulations are used throughout all the process. The
use of MD simulations looks like an obvious step in refining such models. Simulation would
allow the structure to adapt to the new sequence, and in theory give a more realistic model.
Although this point is reasonable as a concept, MD simulations require systems to be close to
their equilibrium (native) conformation. Otherwise, significant and difficult to detect artifacts
may occur. Critical assessment of protein structure prediction contests, where prediction
algorithms face problems with known but nonpublic 3D structures, provide an excellent dataset
to test this issue. Applying different MD approaches to the refinement of such predictions has led
to a number of conclusions
5. Conclusion
MD simulations have already more than 40 years of history. However, it was not until the recent
years that MD has achieved time scales that begin to be compatible with biological processes. At
present, when routine simulations are approaching the microsecond scale, conformational
changes, or ligand binding can be effectively simulated. The improvement of the computational
equipment, especially the use of GPUs, and the improvements made in the optimization of MD
algorithms, including coarse-grained ones, allow us to move from the analysis of single
structures, the basis of the molecular modeling as we know it, to the analysis of conformational
ensembles. Conformational ensembles are a much better representation of real macromolecules,
as they account for flexibility and dynamic properties (including all thermodynamic information)
and ease the match with experimental results. Although the shift in concept is clear, and the
technology is coming along, there is still a long way until biomolecular simulations, the
generation of conformational ensembles, would become a routine. Tools exist that make the
setup of a macromolecular system much easier, and even allow the nonexperts to enter the
simulation world. However, lack of representation standards, much less optimized analysis tools,
and even the difficulties in simply storing and transmitting the huge amount of trajectory data
that is generated are still issues that remain to be solved. In any case, MD is already a valuable
tool in helping to understand biology.

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