MOLECULAR MECHANICS AND DYNAMICSMOLECULAR MECHANICS AND DYNAMICS

Presented by

Mr. Chikhale Hemant U.

M. Pharmacy- Semester II

(Pharmaceutical Chemistry)

Guided By-

Dr. Amit G. Nerkar

Associate Professor in

Pharmaceutical Chemistry

STES’s Smt. Kashibai Navale College of Pharmacy, Kondhwa (Bk), Pune-411 048

Content of the presentationIntroduction to computational chemistryIntroduction to computational chemistry

Need to studyNeed to study

Molecular mechanicsMolecular mechanics

Basic principle of molecular mechanicsBasic principle of molecular mechanics

Semiemperical methodsSemiemperical methodsParameterizationAlgorithmsMolecular dynamicsSimulation technique in molecular dynamicApplication of simulationReference

Introduction to computational chemistry:Computational chemistry is a branch of chemistry that uses principles of computer science to assist in solving chemical problems. It uses the results of theoretical chemistry, incorporated into efficient computer programs, to calculate the structures and properties of molecules.Since chemistry concerns the study of properties of substances or molecular systems in terms of atoms, the basic challenge facing computational chemistry is to describe or even predict

1. The structure and stability of a molecular system, 2. The (free) energy of different states of a molecular system,

3. Reaction processes within molecular systems

Need to study:Because of the complexity of biological systems, computer methods Because of the complexity of biological systems, computer methods have become increasingly important in the life sciences. have become increasingly important in the life sciences.

With faster and more powerful computers larger and more complex With faster and more powerful computers larger and more complex systems may be explored using computer modelling or computer systems may be explored using computer modelling or computer simulations. simulations.

Various simulation techniques such as Various simulation techniques such as molecular mechanicsmolecular mechanics (MM) (MM) and and molecular dynamicsmolecular dynamics (MD), Monte Carlo, and Brownian dynamics, (MD), Monte Carlo, and Brownian dynamics, as well as hybrids of these methods, have emerged as simplifications as well as hybrids of these methods, have emerged as simplifications of the exact quantum mechanical description for large molecules.of the exact quantum mechanical description for large molecules.

Molecular mechanics:The "mechanical" model developed to describe molecular structures and properties in as practical manner as possible

Molecular mechanics methods are based on the following principles:

Nuclei and electrons are lumped into atom-like particles.Atom-like particles have a net chargeInteractions are based on springs and classical potentials. Interactions must be pre-assigned to specific sets of atoms.

Interactions determine the spatial distribution of atom-like particles

and their energies.

BAS IC PRINCIPLES OF MOLECULAR MECHANICS : Empirical force-field methodology is based on classical mechanics and on the assumption that the total “steric” energy of a structure expressed as a sum of many interaction viz,

Another important assumption is that the force-field and its parameters determined a set of molecules and are used to study other molecules.

With the advent of computers chemists have realized the utility of carrying out simulations and studies on various chemical systems using the computer as a tool.

Energy = S tretching Energy + Bending Energy + Torsion Energy + Non-Bonded Interaction Energy

What is a Force Field? A force field is a mathematical function in which the conformational

energy of a system studied. Force fields are also sometimes referred to as potentials. Many different kinds of force fields have been developed over the

years.

Some force-fields account for coupling between bending and stretching in adjacent bonds in order to improve the accuracy of the

mechanical model.

E = Es + Eb + Eω + Enb + …Where:E- The steric energy . Es- Bond stretching Eb- Bond angle bending Eω- Torsional energy Enb- Non bonded interactions .

Stretching Energy :The stretching energy equation is based on Hooke's law. The "kb" parameter controls the stiffness of the bond spring, while "rO" defines its equilibrium length. Unique "kb" and "ro" parameters are assigned to each pair of bonded atoms based on their types (e.g. C-C, C-H, O-C, etc.). This equation estimates the energy associated with vibration about the equilibrium bond length.

Bending Energy : The bending energy equation is also based on

Hooke's law. The "kθ" parameter controls the stiffness of the angle spring,

while "θ" defines its equilibrium angle. This equation estimates the energy associated with vibration about the equilibrium bond angle

Torsional energy :Torsional energy :

Is primarily Is primarily used to correctused to correct the the remaining remaining energy termsenergy terms,, Represents the amount of energy that Represents the amount of energy that must be added to or subtracted from themust be added to or subtracted from the Energy termsEnergy terms to make the total energy. to make the total energy.

Non-Bonded Energy :Non-Bonded Energy :The non-bonded energy The non-bonded energy accounts for accounts for repulsionrepulsion, , van der Waals attractionvan der Waals attraction, and , and electrostatic interactions. electrostatic interactions.

van der Waals attraction van der Waals attraction occurs at short occurs at short rangerange, interacting atoms move apart by a , interacting atoms move apart by a few Angstroms.few Angstroms. Repulsion occurs when the Repulsion occurs when the distance distance between interacting atoms becomesbetween interacting atoms becomes less less thanthan their contact their contact radii radii

Chemical effect:-Chemical effect:-Mechanical effectMechanical effect, such as , such as stretching, bendingstretching, bending, and , and torsiontorsion, , electrostatic electrostatic interactioninteraction are are not sufficient to reproducenot sufficient to reproduce structural structural or or spectroscopic spectroscopic

phenomenaphenomena such as the such as the Electro negativity, Anomeric, Electro negativity, Anomeric, andand Bohmann effect Bohmann effect

Electro negativity:Electro negativity:An examination of chemical-bonding effect indicates that the An examination of chemical-bonding effect indicates that the length of a particular bond is highly dependent on the length of a particular bond is highly dependent on the electronegativity of the attached substituentselectronegativity of the attached substituents bond length of 1.524 A0

Anomeric:Anomeric:Best known in cyclic carbohydrate compounds and Best known in cyclic carbohydrate compounds and derivatives. anomeric effect have been suggested, ranging derivatives. anomeric effect have been suggested, ranging from unfavorable dipole-dipole interaction to n-σ* molecular from unfavorable dipole-dipole interaction to n-σ* molecular orbital.orbital.

Bohmann effectBohmann effect:

The length of C-H bonds adjacent to atoms bearing at least one lone pair of electrons (e.g. amine, alcohol, ethers, and fluorides).

Semiemperical Semiemperical method:-method:-SSemiempirical methods serve as fast quantitative tool for computing a emiempirical methods serve as fast quantitative tool for computing a properties related to molecule.properties related to molecule. Useful for correlating large sets of experimental and theoretical dataUseful for correlating large sets of experimental and theoretical data, ,

Disadvantage But they are alsoBut they are also less accurate less accurate, with errors that are less systematic and , with errors that are less systematic and thus thus harder to correctharder to correct..

Semiemperical method:-

CNDO Method (Complete Neglect of Differential Overlap)

INDO Method (Intermediate Neglect of Differential Overlap)

NDDO Method (Neglect of Diatomic Differential Overlap)

MNDO Method (Modified Neglect of Differential Overlap)

CNDO method :-CNDO method :- The complete neglect of differential overlap method (CNDO) of The complete neglect of differential overlap method (CNDO) of pople et.al makes use of the zero differential overlap approximation pople et.al makes use of the zero differential overlap approximation (ZDO) for all pairs of atomic functions.(ZDO) for all pairs of atomic functions.

It treats explicitly all valence electrons (e.g. 2s, 2p), CNDO/S method that is parameterized to reproduce electronic spectra.

INDO method :-INDO method :-The intermediate neglect of differential overlap (INDO) method was The intermediate neglect of differential overlap (INDO) method was at one time used for organic systems.at one time used for organic systems.

It gives unsatisfying results for geometries and dissociation It gives unsatisfying results for geometries and dissociation energies and replaced by severalenergies and replaced by several improved versions namely, improved versions namely, MINDO/3, INDO/S, and SINDO1.MINDO/3, INDO/S, and SINDO1.

The first of these newer INDO methods is MINDO/1 and MINDO/2. The first of these newer INDO methods is MINDO/1 and MINDO/2.

NDDO- method-NDDO- method-The method Negelect Of Diatomic Differential overlap (NDDO) was The method Negelect Of Diatomic Differential overlap (NDDO) was originally developed by Pople and Beveridge et.al.originally developed by Pople and Beveridge et.al. In principle NDDO- give an improved description long range intra In principle NDDO- give an improved description long range intra and inter-molecular forces as they become important in large and inter-molecular forces as they become important in large bimolecularbimolecular

MNDO methodMNDO method – –

Modified Neglect Of Diatomic Overlap (MNDO) method introduced by Dewar and Theil. MNDO was originally developed for first-row element (H, C, N, O and F). Later extended by Theil and Voiytuk to second row element and transition metal.

The inclusion of orthogonalization correction the INDO method and SINDO leading to the two models OM1 and OM2 (Orthogonalization model 1and 2) respectively.

Parameterization :-All semiempericals contains parameter. They either replace integrals that are calculated analytically or they are part of empirical formulas that describes the chemical bonding

Classification of parameter:

Experimentally derived fixed parameters Adjustable parameter

The orbital energies of valence and inner orbital

Atomic parameter

Bond parameter

Algorithms:-Algorithms:-The algorithms fall into three broads categories.The algorithms fall into three broads categories.

1. The active analog approach and receptor2. Distance Geometry:3. Boltzmann jump:4. Chemometrics

methods:

Programs that suggest a bioactive conformation given the set of matching point.

Programs that are devoted to discovering both the matching points and the proposed bioactive conformation

Programs that are devoted to discovering both the matching points and the proposed bioactive conformation but perform 3D-QSAR analysis

Algorithms

1. Clique detection:2. Genetic algorithm:3. Partial least squares:4. Constrained conformational

search:

1. Gibbs sampling of pharmacophore bitmaps2. EGSITE 3D-Model of binding sives:3. Methods to used pharmacophore feature in QSAR (CoMFA, CoMSIA)

3.3. The active analog approach and receptor :The active analog approach and receptor : SAR information is necessary to proposed the points to match in SAR information is necessary to proposed the points to match in

molecule.molecule. Perform rigid rotation of all rotatable bonds in each molecule,Perform rigid rotation of all rotatable bonds in each molecule, Tabulating distance between the atoms or points of interest are Tabulating distance between the atoms or points of interest are

occupied by a conformation of reasonable energy. eg.occupied by a conformation of reasonable energy. eg. AUTOFIT AUTOFIT6969, , COMPASSCOMPASS163163, ChemDBS-3D., ChemDBS-3D.

2. 2. Distance Geometry: Distance Geometry: Distance geometry is a conformational search strategy in which Distance geometry is a conformational search strategy in which

the algorithm starts with a matrix of allowed interpoint (usually all the algorithm starts with a matrix of allowed interpoint (usually all interatomic) distances. interatomic) distances.

The advantage of distance geometry over rigid rotation is that The advantage of distance geometry over rigid rotation is that ring conformations, bond length, and bond angle not change.ring conformations, bond length, and bond angle not change.

Programs that suggest a bioactive conformation given the set of matching point.

3. Boltzmann jump:3. Boltzmann jump: In this the conformation which has minimum energy it is In this the conformation which has minimum energy it is retain.retain.

Higher energy conformation retained with a probability equal Higher energy conformation retained with a probability equal to the Boltzmann factor е to the Boltzmann factor е ∆E/ RT∆E/ RT

the search allows to overcome torsional barriersthe search allows to overcome torsional barriers..

4. Chemometrics methods:4. Chemometrics methods: In this the principal component analysis and the cluster In this the principal component analysis and the cluster analysis technique are use.analysis technique are use.

The conformation and distance geometry studied by this The conformation and distance geometry studied by this method.method.

1. Clique detection :1. Clique detection : Identify the maximum common 3D substructure in a set of molecule.Identify the maximum common 3D substructure in a set of molecule. For pharmacophore mapping required two changesFor pharmacophore mapping required two changes

5.5. Considering multiple conformations.Considering multiple conformations.

6.6. Defining the pointsDefining the points

2. Genetic algorithm: 2. Genetic algorithm: Performs its search by analogy to biological evolution.Performs its search by analogy to biological evolution.

Genetic operators of mutation and crossover operate to optimize some Genetic operators of mutation and crossover operate to optimize some fitness (scoring) function for the whole set of individualsfitness (scoring) function for the whole set of individuals..

3. Partial least squares: (PLS)3. Partial least squares: (PLS) In PLS one provides the potency of each molecule and sets of CoMFA In PLS one provides the potency of each molecule and sets of CoMFA

descriptors for each potential alignment.descriptors for each potential alignment. PLS identifies the overlay and conformation of the reference compounds PLS identifies the overlay and conformation of the reference compounds

that best explains the biological potency of the compounds. This overlay that best explains the biological potency of the compounds. This overlay was then used to generate a traditional CoMFA,was then used to generate a traditional CoMFA,

Programs that are devoted to discovering both the matching points and the proposed bioactive conformation

1. Gibbs sampling of pharmacophore bitmaps: 1. Gibbs sampling of pharmacophore bitmaps: Bitmap or fingerprint describes the presence or absence of Bitmap or fingerprint describes the presence or absence of

particular geometric featureparticular geometric feature Advantage of the Gibbs sampling is that it detect binding Advantage of the Gibbs sampling is that it detect binding

modes that is necessary.modes that is necessary.2. EGSITE 3D-Model of binding sieves :2. EGSITE 3D-Model of binding sieves : The algorithm start by placing all molecule into an uniform The algorithm start by placing all molecule into an uniform

macromolecular binding site, macromolecular binding site, Then fits the ligands into complementary region by changing its Then fits the ligands into complementary region by changing its

orientation in space orientation in space and its conformation.and its conformation.3. Methods to used pharmacophore feature in QSAR:3. Methods to used pharmacophore feature in QSAR: To evaluate or use pharmacophore for alignments in 3D-To evaluate or use pharmacophore for alignments in 3D-

QSAR such as CoMFA, QSAR such as CoMFA, Several program make specific use of pharmacophore feature Several program make specific use of pharmacophore feature

in a 3D-QSAR to search for pharmacophore,in a 3D-QSAR to search for pharmacophore,

Programs that are devoted to discovering both the matching points and the proposed bioactive conformation but perform 3D-QSAR analysis

MOLECULAR DYNAMICS: (MD)

First simulation methods

The 1970s MD has been used widely to study the structure and dynamics of macromolecules

Resembling very much the ‘ball and stick’ model

Molecular dynamics is concerned with molecular motion

Simulation technique in molecular dynamic :

Used to st the behavior study multiple-particles systems via numerical simulation techniques.

The principle is to compute positions and velocities of the atoms

Simulations has importance in biochemistry and molecular biology, where they allow functional observation of proteins, nucleic acids, membranes, and other building blocks of the cell

A number of established MD simulation Molecular dynamic simulation, Monte Carlo, CHARMM, AMBER, GROMACS used for calculation.

Molecular dynamics simulation

The time-dependent behavior of a molecular system studied such as vibrational motion or Brownian motion. Compute the energy of the system, most often using a molecular mechanics calculation. This energy expression is used to compute the forces on the atoms for given geometry.

MONTE CARLO Simulation :

In which the location, orientation and geometry of a molecule or group of molecules are chosen according to a statistical distribution Require less computer time to execute each iteration than a molecular dynamics simulation.

AMBERAssisted model building with energy refinement (AMBER)It was parameterized specifically for proteins and nucleic acidsCHARMM

Chemistry at Harvard macromolecular mechanics (CHARMM).

The academic version of this program is designated CHARMM and the commercial version is called CHARMm

It was originally devised for proteins and nucleic acids. ·

GAUSSAIN – Able to perform molecular mechanics calculations on single molecules. Includes molecular dynamics and structure optimization.

GROMACS – GR Oningen MAchine for Chemical Simulation

GROMACS help in obtaining high throughput. originally developed for nucleic acid and protein molecule

Application of Simulations: Understanding in Terms of Atomic Properties

Interpretation of Biochemical Data, Binding by MD Computer Simulation

Interpretation of Biophysical Data on membrane Properties by MD Computer Simulation

Determination of Spatial Molecular Structure on the Basis of 2D-NMR, X-Ray Diffraction Data

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Holtje H. D., Wolfgang S., et .al., Molecular modeling basic principles and application, computational tools for geometry optimization. Second edition, Wiley-VCH GmbH & Co. Page no.15,16

Theil W. et.al., Modern Methods and Algorithms of Quantum Chemistry, 2000. Second NIC Series, Vol-3. page no. 261-283.

Bowen J.P., Liang G., New vista in molecular mechanics Practical application of computer aided drug design, edited by Charifson P.S. Marcel Dekker INC. page no-515,519