Upload Now
In this article we will discuss about the meaning and applications of molecular modelling.
Meaning of Molecular Modelling:
Molecular modelling is a group of techniques that employ computer-generated images of chemical structures that show the relative positioning of all the atoms present in the molecule being studied, and/or the simulated dynamics of such molecules together with their ordering through space-time.
Such techniques are of considerable help for understanding many physicochemical properties of molecules, and may also provide clues about their possible role(s), that is, their function, in the organism. They can be thus especially valuable tools for investigating structure-function relationships.
Proteins-within a given protein family-have, in theory, similar sequences and generally share the same basic structure. Thus, once the structure for one member of the ‘protein family is determined, molecular modelling computations can help determine the structure for other members of the same protein family.
Such a homology technique when applied to protein structure may allow scientists to gain additional insight into protein structure, especially for those proteins for which the available experimental data is scarce.
Structures of Apolipoprotein:
Lipoprotein in mammals has evolved as the primary transport vehicles for lipids. This role leads to the importance of lipoproteins in several diseases, such as atherosclerosis and cardiovascular disease. Lipoprotein particles consist of a core of neutral lipids, stabilised by a surface monolayer of polar lipids complexed with one or more proteins.
Apolipoprotein A-I and apo B are respectively, the major protein components of high density (HDL) and very low density (VLDL) lipoproteins. Thus, understanding apolipoproteins is very important for medical and health-related fields, such as medical biotechnology, as well as food science and human nutrition.
The process of biosynthesis, the physical characteristics and the metabolism of apolipoproteins have been intensely studied. However, because of the noncrystalline structure of many apolipoproteins, it has been difficult to obtain structural data at the molecular, or atomic, level. Therefore, methods combining the amino acid sequence with molecular methods are now being introduced.
Thus, overall structures may be derived from correlations of global secondary structures determined from polarised light studies combined with local structures predicted from amino acid sequences. The known amino acid sequence of apolipoprotein from the position 7 to 156 of apo Lp-III was first used to design an Apo A-I template, that could be then approached by ‘standard’ molecular modelling techniques.
Molecular Modelling of Apolipoproteins A-I:
Target:
Apolipoprophorin III is chosen as a target for apolipoprotein A-I. (apo Lp A-I). The structure of Apolipophorin III has been determined in a crystal at 2.5Å resolution for the 18-kDa apo Lp III from the African migratory locust, Locusta migratoria and the 22-kDa Nterminal, receptor-binding domain of human apo E.
Template for Apo A-I:
Lp IIIa is designed by using molecular software IALIGN from Lp III by inserting alanine for template of sequences of apo A-I (using the programme SYBYL, V5.5). Alanine residues are inserted at each of the gap position identified by IALIGN, an interactive alignment programme distributed with the Protein Identification Resource (PIR).
This model was compared with DgA-I, HuA-I and ChA-I resprsenting canine, human and chicken Apo A-I respectively. Results were then compared using a “strip of the helix” template by scoring 1 or 0 for residues that did, or did not, fit into the template.
Modelling results:
i. Sequence Comparison:
The five long a-helices connected by short loops in amino acid residues 7-156 of apo Lp-III is used as template for LpIIIa, Dig A-I, DgA-I, HuA-I. Amphipathic potential (AP) is used to detect if the predict structure is suitable for a lipid-aqueous interface in its stable condition.
ii. Energy minimised models:
In these model, electrostatic interactions contributes the most to favourable energies. Alanine was chosen as the spacer residue in building apo Lp-IIIa because of its function of small, non-ionic side chain and serves as a helix-stabilising residue.
Although it has a high probability of being found in helical structures, it does not participate through electrostatic interactions. Results of this model are discussed for potential energetic evaluation and amphipathic analysis of energy refined helices.
After evaluating the potential energy for this model, the lateral view structures of apolipoproteins for apo lipophorin III (residues 7-156), canine apolipoptrotein A-I (residues 72-236), human apolipoprotein A-I (residues 73- 237) and chicken apolipoprotein A-I (residues 72-236).
Combination of Molecular Modelling with other Techniques:
It is important to combine molecular modelling with other techniques in order to improve the accuracy of the modelling results. A recent study of Apolipoprotein has produced a highre solution reconstruction of the structure of apolipoprotein through combination with a solution phase X-ray technique.
It was shown that Apoliproprotein A-1 is an 243-residue protein that contains a globular amino-terminal domain (residue 1-43) and a lipid-binding carboxyl-terminal domain. The aqueous phase X-ray crystal structure was obtained at 4A resolution. This has suggested the accuracy of molecular modelling by combining the X-ray crystallographic with molecular modelling.
Analysis of Molecular Model:
The determination of apolipoprotein A-I can be then further associated with lipid containing domains by employing other molecular modelling techniques. The ‘belt model’ is used to show the possible orientations of lipoprotein with its apolipoprotein inserted. The suggested structure can then serve as a template in other high density lipoproteins for their structure determination and also help in understanding the biological interaction.
Applications of Molecular Modelling:
Molecular modelling has been introduced for more than two decades ago. Increasingly, modelling software is available for a variety of industrial applications. Global markets for molecular modelling, in general, now exceed 2 billion US $ annually.
Applications in the food industry:
Molecular modelling has been suggested by several professionals in food industry as a new tool for food research. Such tools can assist food scientists in problem solving, as well as save time and money.
Examples of utilisation of molecular modelling are the uses of high intensity sweeteners and taste receptors to predict the sweetening potential of new molecules by using molecular modelling as developed by and E.W. Taylor and S. Wilson at the University of Georgia. Such models can be used in food industry for product development and also for faster results in sensory evaluation.
Medical Applications:
Molecular modelling is especially helpful in medical fields, such as in development of new drugs on a nano-scale. Recent studies have shown the importance of using molecular modelling in both medical and food sciences. The molecular modelling of Epigallocatechin Gallate (EGCG) and the HIV cell was undertaken by Shearer.
His report has inspired scientists in Japan who discovered the potential of green tea as an anti-HIV drug. The chemical compound that is found abundantly in the green tea called Epigallocatechin Gallate (EGCG) is reported to stop the HIV virus from binding to CD4 molecules and human Tcells.
Other applications:
Other applications of molecular modelling to manufacturing, life sciences and chemistry greatly benefit from such molecular modelling programmes. Nanotechnology has developed to a 30 to 40 million US $ market, and it also has the potential to grow to a 60 to 70 million US $ market within the next five years.