History Of Molecular Modeling

Published Date: 02 Nov 2017

Molecular modeling is one of the most rapidly growing fields in biology and science. The study of molecular modeling has been proven to be immense since until now the technology of molecular modeling is still evolving. Having the potential to impact biology, medicine, and technology it is very clear that molecular modeling is very successful as one of biological field which helps scientist and researchers to understand structures of a subject at molecular level.

Molecular modeling is the science and art of studying molecular structure and function based on structure determination and structure prediction through model building and computation. The model building can be as simple as plastic templates or metal rods, or as sophisticated as interactive, animated color stereo-graphics and laser-made wooden sculptures, or a 3 Dimensional computer graphic model. The computations part involve a bit more calculations with algorithms and it can be divided into many fields such as, empirical (molecular) mechanics, visualization, homology modeling, docking, molecular dynamics (MD), Monte Carlo, ab initio and semi-empirical quantum mechanics, free energy and solvation methods, enhanced sampling and pathway methods, principal component analysis (PCA), structure/activity relationships (SAR), chemical/biochemical information and databases and many other established procedures and methods.

Many researchers, scientist, chemist, and even students like to prefer using molecular modeling in order to understand the properties of molecular structures. This is because modeling is very flexible and it can clearly provide a way to systematically explore structural, dynamical, and thermodynamic patterns. Furthermore by using modeling, they can test and develop hypotheses to help understand and extend basic laws that govern molecular structure, flexibility and function. In terms of usage, molecular modeling has been applied to various kinds of fields such as drug designing, water treatment, food industries and even as learning materials.

In 1953, the most important breakthrough of scientific diagram is introduced. This is due to the help of a model of DNA molecule. After that bio molecular modeling started to gained momentum in the late 1980s. This is because around that time there is increasing availability of high-speed computers. Furthermore standardized programs and significant technological innovations are introduced also around the same years. However if we travel back through history, molecular modeling can actually be traced back to the 1860, around 153 years ago. During this time August Wilhelm von Hofmann created the first physical molecular model which looks like balls connected together with sticks. There are 4 white balls connected to a black ball in the middle with a metal stick. This model, which is the ancestor of all molecular models have similar characteristic as the ball and stick models which have been massively used today, with some unique features. The first noticeable features would be that the models is connected to a middle carbon which form a square planar since at that time the concept of tetrahedral carbon is still not being introduced yet. The other noticeable features of the size of the carbon atoms (black), is actually smaller than the size of hydrogen atom (white). However this problem is quickly rectified by Josef Loschmidt in 1861.

After the introduction of concept of chemistry in space relatively known as stereochemistry in three dimensions by Jacobus Henricus van't Hoff and Joseph Achille Le Bel, and the creation of the tetrahedral molecules by van’t Hoff in 1874, there are many evolutionary changes occurred to the field of molecular modeling. After the development of X-ray crystallography as a tool for determining crystal structures in 1958, many laboratories built models based on spheres. With the development of plastic or polystyrene balls it is now easy to create such models thus making the balls and stick model really popular. Several years after, the creation of DNA models by Watson and Crick actually introduced another kind of models which is the skeletal model. These models are created based on atomic components where the valences were represented by rods and the atoms were points at the intersections. The bonds were created by linking components with tubular connectors with locking screws. After that, a polyhedral model is introduced, followed by the introduction of the composite models and CPK space-filling models which is developed in 1965.

Only after the creation of various models and an increasing need for integrating the view of molecular structure in many models, a computer based models is introduced. This concept is first used in 1970’s and rapidly gained momentum in 1980’s. Nowadays the computer based models is one of the most popular and widely used around the world. This is because there are several advantages of using computer based models compared to using physical models. Some of these advantages are like it is geometrically more accurate, capability to make precise calculations and it is easily stored, edited and duplicated.

Molecular Graphics and Molecular Viewers

Molecular graphics is the discipline and philosophy of studying molecules and their properties through graphical representation. In a much simpler meaning, a molecular graphic is the representation of molecular structure on a graphical display device. Molecular viewers in other hands are the tools which are used to display or visualize the molecular graphics by the means of computers. These tools allow the visualization of molecular structure in many formats such as 2D and 3D. Molecular viewers have the capability to view more than one kind of models depending on the need. Advance molecular viewer have the ability to calculate, make comparison and allows many more operations done to the models such as zooming in or out, view certain molecule only, and many more.

In terms of which is the best way to visualize a model, either by physical or by molecular graphics is depending on the users and situations, since both of them have their own strength and weaknesses. Sometimes people does prefer to use the physical model as it can be viewed anywhere without the need to use a computers. They can be manipulated easily with the hands and it can show the molecule rotations ability easily. Furthermore by using the physical model, the structure of the molecule can be appreciated more than using computer model. However given the size of the models sometimes is can be very hard to create, store and carry the physical models. This is where the molecular graphics plays its part. With the computer, it is easier to store, share and create large molecules with precise measurement with little errors.

It is very important to know the issues of the complexity of biological systems and try to tackle those issues effectively with the help of molecular modeling. One of the most essential aspects to tackle these issues is decision making and one of the key aspect of decision making in bio molecular modeling is to choose an appropriate method which is suitable for the chosen particular systems and the chosen questions of interest. The most important aspect of choosing a method is to choose the one that should be capable of delivering a reliable result in a reasonable time. One of the most successful approaches to date on structure prediction comes from homology modeling (also called comparative modeling).

There are many bio molecular modeling models which have been created throughout the development of molecular modeling. Let’ go through these models in order to know more about them in details. The first model is known as the Space filling models. Space fillings model get their name by their model representation which looks like a ball which have been clumped together. These balls are actually atoms which are drawn as solid spheres to suggest the space they occupy. The surface of these balls or models to be exact is the representation of the level of density of electron clouds. There are 4 types of space filling models which is the Van der Waals model, Solvent Accessible model, Molecular Surface model, and Molecular Skin model. In the Van der Waals model, the atoms are represented as disk, and each of them is specified by its radius and center point. Each of these atoms can be identified by its type and locations in space. A Solvent Accessible model is represented as omnipresent sphere where it is represented by the interactions between the Van der Waals models and a solvent. The value of each Van der Waals disk is increased by a constant which is the radius of the solvent. The Molecular Surface models combine the concept of Van der Waals model and the Solvent Accessible models. It use the size from the Van der Waals and use the connectivity from the Solvent Accessible model to create a results that would look something like a disks covered with rolls of solvent. The last type of Space Filling models would be the Molecular Skin models which look like many balls which shrink and being compressed together with their neighbors and create a looks of a skin.

The other model is known as Dual Models. These model actually a space filling model with a common dual counterpart. These space filling models can be the union of either Van der Waals or Solvent Accessible model. To construct a Dual Model, a diagram called Voronoi Diagram which use the concept of Voronoi Cells is created. These cells are actually the imaginary representation of the balls from the space filling models. The cell is the region of points whose weighted distance to a point is at least as small as the other cells. Voronoi cells are also known as Thiessen Polygon, Power Cells, and Dirichlet Cells. Then a better representation of the model called Delaunay Complex is introduced. The Delaunay Complex is the collection of simplices that can show the record of the overlap pattern of the Voronoi Cells. The Delaunay Complex looks something like a 3D terrain wireframe. A better type of the models from the Delaunay Complex would be the Alpha shape which looks something like a diamond, which overlaps on union of balls. The Alpha Shape restricts the construction of simplices o the portion of Voronoi cells covered by the atom balls. The alpha is actually representing a parameter that expresses the growth of the balls. After the Alpha Shape is created, then a Duality models can be created from the dual union of the balls.

A molecular graphics have some functions that can check for connectivity, and check for the structures geometric sizes by using some formulas such as truncated formula and angle-weight formula. Some of the examples of the connectivity are the voids and tunnels in the biomolecules. To check the connectivity, a molecular graphic can be used to identify the void by checking the dual simplex sets. The Delaunay Complex can be used to check the pockets and the holes can be computed and counted by using mathematical algorithms. It is mentioned earlier that there is a connections between the topological complex representations of a molecule and its geometric size. There are several formulas which are used in order to get the volume size of a molecular structure. The first one would be the Inclusion-Exclusion method which expresses the volume of the union of balls as an alternating sum of volumes of common intersections. The second one would be the truncated formulas which can give the exact volume of a Delaunay simplex in the alpha complex. The last one to be discussed is the Angle-Weight formulas. This formula can compute the volume of a void in molecular structures.

Some of other things that we can observe by using the molecular graphics and molecular viewer are the metamorphosis of the structures. There are some condition in which the structure would have gone metamorphosis such as growth, motions, and space of shapes. The simplest form of metamorphosis would be the growth of the molecule. Then there would be motion which makes the molecular shape deformed because of the atoms balls is radically moving which in turns create motions. The possible example of the applications of the general motions would be the visualization of the folding process. The last kind of metamorphosis would be the space of shapes. The idea is based on the ability to deform the molecular shapes. The ability to canonically deform a shape opens up to the possibility to construct the space of shapes. Simply said, it uses a single parameter to control the deformation from one shape to another.

Other observational features which can be viewed by molecular graphics and molecular viewer would be the rotations, folding patterns, planar, bonds, angles and length of the molecular shape. Although all of these can actually be viewed by the physical model, it is actually more accurate to use the molecular graphics.

Protein Structure With Reference to Hemoglobin and the Prion Protein

Structure is a construct and arrangement of relations between the parts of elements to give patterns or organizations to something complex. Protein is basically made from a long chain of amino acids. There are many types of amino acids, however only 20 are needed in order to create the human protein. There are many kinds of proteins, each with their own specific functions. A protein structure is the 3 Dimensional structure of a protein which is the biomolecular structure of a protein molecule. One of the most important experimental techniques for studying protein structure to date has been the X-ray crystallography. In order to do the X-ray crystallography a well-ordered crystal is needed. However finding appropriate crystallization conditions can be difficult, particularly for membrane proteins.

Protein structure is one of the most important bases of living organism which coordinates the functional property of cells to sustain life. Every function and every action done inside of the body is dependent on proteins. In order to understand more about protein structure we need to know the type of structures inside a protein and what kind of elements that is important inside the protein structure. Proteins are not just randomly a coiled chain of amino acids. Proteins consist of 4 levels of organizations which are actually caused by the variety kind of protein folding to give a 3 Dimensional structure and shape. There are primary structure, secondary structure, tertiary structure and a quaternary structure. Furthermore there are many elements inside these structures such as α-helix, the β strands, turns, loops, coiled coils, and peptide bonds which can be used to describe the structures further.

The primary structures of a protein are actually just amino acids which is stacked together to form long chains. Just one change of the amino acid positions can leads to a critical alternation of the functions and activity of the proteins. The amino acids are connected to each other in a head-to-tail fashion by formation of a peptide bond by the process of condensation where the water molecule is removed. When there are 2 amino acids connected the bond would be called as dipeptide bond while 3 amino acids are connected by tripeptide bond and so on. With an increasing number of acids in the sequence, the molecules are referred to as oligopeptides and polypeptides.

Secondary structures of proteins are actually the local conformation of the polypeptide chain or the spatial relationship of the amino acid residues which are placed close together in the primary sequence. This organizational level is found in globular proteins where three basic units of secondary structure are present, namely, the α-helix, β-strand and turns. The α-helix is the most common structural motif found in proteins and since there are about 30% of helix structures in the globular proteins, it is the most identifiable units among the secondary structures element. An α-helix is a right handed coils which is held together by hydrogen bonding of carboxyl group, amino group and the R-group. The β-strand or also known as β pleated sheet is actually two polypeptide backbones which are folded and aligned next to each other. They are connected via hydrogen bonds.

Other than that, there is also an element known as turns. Turns are secondary structural elements where the polypeptide chain reverses its overall direction. Then there are loops which connect the secondary structure elements of the polypeptide chain. Loops form a compact globular shape of the protein which contain polar residues and hence, predominantly occur at the protein surface which contributes to the formation of active sites for ligand binding or catalytic activity. Loop structures that are random are less stable and referred as random coils. A coiled coil is a structural motif in proteins in which is tightly packed together and form a heptad repeat. The coiled coil element is responsible for the amphipathic structures.

A tertiary structure is looks something like a 3 Dimensional images of the protein which clearly can show the folding of the polypeptide chain in 3D space. It can be grouped into domains which is the sections of the protein folded in order to represent structurally distinct unit. Each domain usually exhibit specific functions. Domain regions may be α-helices or β-strand or mixed elements of both. The specific folding of a protein is only thermodynamically stable within a restricted range of environmental parameters, i.e. the right temperature, pH and ionic strength. Outside of this range, the protein could unfold and lose its activity. Motif is a supersecondary structure, which also appears in a variety of other molecules. Motifs do not allow us to predict the biological functions yet they are found in proteins and enzymes with dissimilar functions.

The quaternary structure is the further compactions and folding of the tertiary structure to create a multi subunit complex. The quaternary structure describes how these different chains and components interact and connect to each other by hydrogen bonding, electrostatic attraction and sulfide bridges. Therefore, the quaternary structure refers to the noncovalent, stable association of the multiple subunits. A classic example of a protein that exhibits quaternary conformation is hemoglobin, DNA polymerase, and ion channels. Earlier it is described that amino acids are joined together by a peptide bond. This bond actually helps to link the amino group of one residue with the carboxyl group. The folding pattern of the polypeptide chain is determined by the rotations and angles around the peptide bond, which make observations around this area quite important.

Protein folding can helps determining the structure of a protein, and can affect the proteins structures depending on situations. One example that shows how protein folding implicates the structure and the functions of the proteins would be phenomena called Protein Misfolding. There are evidences stating that the protein folding enigma are also emerging from another puzzling discovery involving certain proteins termed prions. These misfolded proteins are not triggered by mutations, but it is triggered by a conformational change. There are many kinds of diseases which are linked to this phenomenon. It would appear that this phenomenon is the source of infectious agent in fatal neurodegenerative diseases like bovine spongiform encephalopathy (BSE) or ‘mad cow disease’, and the human equivalent Creutzfeld-Jacob disease (CJD). AN accurate mechanism of protein misfolding induced diseases is not known.

Prions are an infectious agent which composed of proteins and their structure is in a misfolded forms. It is a microscopic protein particle similar to a virus but lacking nucleic acid. It does not self-replicate (unlike a virus) and the process is dependent on the presence of the polypeptide in the host organism. Prions are hypothesized to infect and propagate by refolding abnormally into a structure which is able to convert normal molecules of the protein into the abnormally structured form. There are possibilities that certain proteins and prions carry genetic instructions which is actually a role traditionally attributed to nucleic acids. All known prions induce the formation of an amyloid fold, in which the protein polymerizes into an aggregate consisting of tightly packed beta sheets. This altered structure is extremely stable and accumulates in infected tissue, causing tissue damage and cell death. This stability means that prions are resistant to denaturation by chemical and physical agents, making disposal and containment of these particles difficult. Now comes the important questions. Is the prions considered as infectious proteins? Is it possible for an ailment to be transmitted by ‘infectious proteins’ rather than viruses or other traditional infectious agents? The prion interpretation for the infection mechanism remains controversial for lack of clear molecular explanation so uncertainties appear to remain. Some scientists believe that a lurking virus or virino (small nonprotein-encoding virus) may be involved but no such evidence has yet been found.

Protein Database

A database is an organized collection of data which is ordered in such a way that a computer program can quickly access the desired pieces of the data. The concept is the same as the old filing systems except that it is used by the computer and can store and access data quickly in one place. A protein database is actually an archive which contains information about the well-researched structure of proteins. Usually these databases will not only contain information for protein but also information of nucleic acids and complex assemblies. There are many protein databases which have been created nowadays and they can be classified into several types depending on their levels of information and the nature of the database itself. There are primary databases, secondary databases, composite protein sequence database, and structure classification database.

The primary protein database is the most all-purpose database of proteins. This database contains general information about the proteins such as descriptions of functions, papers, publications, domain structures, and protein sequence data. Some of the most popular primary protein databases include PIR (Protein Information Resource), MIPS (Martinsried Institute for Protein sequences), SWISS-PROT, and TrEMBL. There are 3 most important primary databases which is the NCBI, EMBL/EBI and the DDBJ. NCBI stands for National Center for Biotechnology Information and their database is known as the NCBI GenBank. Genbank is a genetic sequence database which has collections of all publicly available nucleotide sequences and their protein translations. GenBank and its collaborators such as EMBL (European Molecular Biology Laboratory) and DDBJ (DNA Data Bank of Japan) receive sequences produced in laboratories throughout the world. Their data ranges from more than 100,000 distinct organisms. In the more than 30 years since its establishment, GenBank has become the most important and most influential database for research in almost all biological fields, whose data are accessed and cited by millions of researchers around the world.

A composite protein sequence database is created for simplifying the sequence search for a protein query in a single compilation. It usually is a database which has better and simplified search function. These databases are non-redundant and render sequence searching much more efficient. Some example of this type of database is like the NRDB (Non-Redundant DataBase) which is the default database of the NCBI, and BLAST (Basic Local Alignment Search Tool) service which acts as the composite for sites like SWISS-PROT, PDB, and GenPept. A secondary database is a website which acts as an analysis tools for the primary database. A database of this kind enhances the primary database searches, by deriving multiple sequence information and assigned the proteins based on these predefined characteristics and patterns. An example of these databases includes Prosite which describe the protein families, domains and functional sites as well as amino acid patterns, signatures, and profiles. Another well-known example would be Pfam which use a Hidden Markov Models to search for protein sequence alignment.

The last level of protein database is the structure classification databases. As the name implies a database of this kind is used to work with protein structures information such as shapes, elements, pictures and evolutionary relations between proteins. These databases usually work on a certain scheme to ensure a certain level of data integrity. Those protein structure classification schemes are known as the CATH (Class, Architecture, Topology, and Homology), SCOP (Structural Classification of Proteins) databases. One most popular example for this kind of database would be the PDB (Protein Data Bank).

The Protein Data Bank is the collection of structures and structural data of proteins, nucleic acids and other biological macromolecules. It is freely available and can be accessed by anyone who can connect to their databases. It was first established in 1971 as a repository for the 3-D structural data at the Brookhaven National Laboratory, New York. PDB is one of the vital resources in molecular modeling. This is also true for the study of structural biology and structural genomics. Most of the PDB structures are contributed by researchers worldwide. Most of them are derived typically from X-ray crystallography, NMR spectroscopy, cryoelectron microscopy and theoretical modeling. PDB therefore serves as a platform to collect, organize and distribute structural information.

The PDB archive contains atomic coordinates, bibliographic citations, primary and secondary structure information, crystallographic structure factors and NMR experimental data. There are various options to view, download and search for structural neighbors. An entry in the PDB contains information about the chemistry of the macromolecule, the small-molecule ligands, some details of the data collection and structure refinement, and some structural descriptors. In all, a typical PDB entry has about 400 unique items of data. The PDB file format that was devised in 1976 is simple, easy to read by humans and used by many computer applications.

The PDB archive is a key example of a community resource that has evolved over its 36 year history. Its evolution has been driven by changes in science and technology used to determine structures, the nature of the structures that are determined, community attitudes about data sharing, and the nature of the communities that are interested in structural data. As the PDB continues to evolve, in addition to being able to use these data to perhaps predict structure, an even greater challenge will be to determine function by knowing the structure. Once accomplished, the long-term vision of enabling a molecular view of biology and medicine will become a reality.