Molecular Biology Techniques in Agriculture: Molecular Modelling

Molecular Modelling
Figure 1. Geometry optimized structures (stick representation) with the electrostatic potential mapped on the isosurface: (A) DOXP,(B) FOSM, and (C) FR-900098 molecules

At the end of the last century, the new computational methods named “molecular modeling” become very popular and extensively used a tool for analysis of molecular structures of a variety of biomolecules and drug design and optimization. A term “molecular modeling” encompasses a variety of different computational techniques including “molecular visualization”, “computational chemistry”, “quantum computational chemistry” and “molecular dynamics”. The latter two are a daily tool in designing and optimization of drugs and analysis of molecular dynamics and structural properties of proteins, and both employ diametrally different physical principles. Quantum computational chemistry employs the rules of quantum chemistry, and molecular dynamics employs standard Newtonian force field. Tremendous progress in both fields of computations has been observed over the last two decades, due mainly to the development of new numerical methods as well as an enormous increase in computer speed. Both techniques also have an enormous impact on economic growth allowing for faster and more efficient drug designing thus improving the health status of both humans and domestic animals. The acquaint the reader with the principles of both techniques I will provide an example of classical quantum-chemical computation and molecular modeling simulation.

Figure 2. The binding of an arbitrarily chosen structure of glucosylceramide (1), conduritol-β-epoxide (2) and glucose (3) to the active site of DOXP-reductoisomeraze: blue mask represents loop1 (Ser345-Glu349) and loop2 (Val394-Asp399), whereas red mask the residues E235 and 340

The first thesis is focused on an analysis of substrate and inhibitors of 1-deoxy-2-xylulose-5-phosphate reductoisomerase (DOXP-reductoisomerase) – the potential novel target molecule for anti-malaria drug development (Zubrzycki and Blatch 2001). In the early years of the XXI century an information emerged that 1-deoxy-2-xylulose-5-phosphate reductoisomerase responsible for isopentyl diphosphate synthesis may be a useful “metabolic place” allowing for the control of development of Plasmodium falciparum and thus allow to eradicate malaria (Disch et al. 1998) – the current plague of humanity leading to the death of one million people per year (UNICEF 2018). The study unfolded physicochemical properties of the two mimetics of the substrate (DOXP), i.e., fosmidomycin (FOSM) and FR-900098. It also provided the interatomic bond lengths and charges that may be of use for further drug optimization and development. Just a visual inspection of the obtained results unfolds similar charge distribution between the substrate and its mimetics as well as an increase in the length of the molecule and higher density in positive atomic charge that may be responsible for inhibiting the action of DOXP-reductoisomerase. Thus, using computational chemistry, we can confirm the structural and physicochemical properties of the newly designed mimetic. We also may obtain the new lead molecules for further drug development.

The second example of the use of computational modeling is the study on the substrate, product, and inhibitor binding to wild-type and neuronopathic forms of human acid-β-glucosidase (Zubrzycki et al. 2007). We know that Gaucher disease is a lysosomal storage disorder caused by a deficiency of human acid β-glucosidase. The study was designed to draw a correlation between the manifestation of disease caused by the specific point mutations at 444 residue of the sequence of the enzyme: they are L444P and L444R, respectively. Making a long story short, the study shows that binding of the substrate is influenced by an interplay of E235 and E334 residues, constituting putative substrate binding site, and the region flanked by D435 and D445 residues. The results of this study suggest that L444P mutation leads to concealment of the hydrophobic core while the L444R mutation to the exposure of the hydrophobic core of the molecule. Both mutations although of entirely different physical property, result in the same neuropathicity and render the enzyme inactive.

Although, both examples are derived from human studies the same scientific scheme applies to the vast area of study in animal samples.

Summarizing, the use of computer-enhanced molecular modeling is a valid tool for drug and molecule analysis of great economic importance.


  • Disch, A., J. Schwender, C. Muller, H. K. Lichtenthaler, and M. Rohmer. 1998. “Distribution of the mevalonate and glyceraldehyde phosphate/pyruvate pathways for isoprenoid biosynthesis in unicellular algae and the cyanobacterium Synechocystis PCC 6714.” Biochem J 333 ( Pt 2):381-8.
  • Zubrzycki, I. Z., and G. L. Blatch. 2001. “DFT study of a substrate and inhibitors of 1-deoxy-2-xylulose-5-phosphate reductoisomerase – the potential novel target molecule for anti-malaria drug development.” Journal of Molecular Modeling 7 (10):378-383. doi: 10.1007/s00894-001-0053-x.
  • Zubrzycki, I. Z., A. Borcz, M. Wiacek, and W. Hagner. 2007. “The studies on substrate, product and inhibitor binding to a wild-type and neuronopathic form of human acid-beta-glucosidase.” J Mol Model 13 (11):1133-9. doi: 10.1007/s00894-007-0232-5.

Author: Igor Z. Zubrzycki PhD

Department of Animal Molecular Biology
National Research Institute of Animal Production
1 Krakowska Street, 32-083 Balice, Poland

An article prepared as part of the ProBio Małopolska project