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Molecular dynamic (MD) simulations have been an integral component of many modern microscopy techniques. These MD simulations are especially useful in elucidating protein function and dynamics. In fact, some of the most important scientific questions in modern cell biology are currently being answered by the combined use of experimental methods, such as programmed algorithms that are used to perform MD simulations, and computational methods.
Despite its potential the use these combined CM techniques has is limited by following three main aspects:
- Short timescales covered by the simulations
- Inability to model large and integral biomolecular systems,
- The actual predictive power of the molecular dynamics methodology1
As a result, the potential of MD simulations alone to make relevant scientific discoveries has remained a topic of debate within the scientific research community1.
Applications of Computational Microscopes in Molecular Modelling Studies
CMs serve as an indispensable tool to model the structures and mechanics of complex molecules. For example, the cage-like structure that encapsulates the genetic material of the human immune virus (HIV) is composed of a large assembly of more than 1,300 identical proteins2. This structure protects the viral DNA until the virus binds to the host cell and injects the DNA into the host cell. In fact, in 2013 Klaus Schulten and his team utilized a program known as Nanoscale Molecular Dynamics (NAMD) in conjunction with CMs to model this complex structure involving 64 million atoms2.
Recent Advances in Computational Microscopy
Researchers at the University of Illinois have recently constructed a computational microscope that has a subatomic resolution. In their work published in Nature Methods, the group of researchers simulated the dynamics of large molecular systems with atomic and subatomic resolution, of which included the binding of amino acid glutamate (Glu) to its transfer RNA2. This process is driven by utilizing the energy generated from the conversion of Adenosine triphosphate (ATP) to Adenosine diphosphate (ADP)2. This novel computational microscope shows great promise and can serve a great deal in understanding the chemistry of life, model large molecular systems and even develop novel pharmaceutical drugs.
Zaida Luthey-Schulten’s team at the University of Illinois, in collaboration with Frank Neese, of the Max Plank Institute for Coal Research in Germany, recently developed an advanced computational microscope by combining two computational approaches, including Nanoscale molecular dynamics program (NAMD) and a program that provides subatomic realm. NAMD utilizes traditional methods to model the structure to predict the behavior of hundreds of millions of individual atoms2. The second program simulates the interaction of subatomic particles including protons, neutrons, and electrons to model the interaction of subatomic particles and to study their behavior.
As one might expect, it requires a lot of computational power to model structures at this resolution, therefore, these researchers used a method to partition such large molecules into classical and quantum mechanical regions2. This approach allows the researchers to focus on tiny regions of the molecules in detail and therefore shed light on critical interactions including the formation and breakage of chemical bonds. Both Klaus Schulten and Luthey-Schulten’s teams utilized the Blue waters supercomputer at the National Center for Supercomputing Applications at the University of Illinois for their molecular dynamic studies2.
tRNAs play a major role in bringing in a series of amino acids to the ribosomes to synthesize new proteins based on the message encrypted in the amino acid sequence. Therefore, tRNAs play a key role in the translation process. In the present study, the researchers demonstrated the chemical behavior of tRNAs. Using the modern computational microscope, Luthey-Schulten’s team modeled the molecular structure of tRNA when a specific protein is loading an amino acid on to the tRNA2.
This team created simulations of four potential scenarios of how this process could occur in a cell and determined that one of these four potential ways would be more energetically favorable, and therefore more likely to occur2. This incredible work carried out at the University of Illinois added subatomic scale to the MD simulations carried out by computational microscopes.
- Lee, E. H., Hsin, J., Sotomayor, M., Comellas, G., & Schulten, K. (2009). Discovery Through the Computational Microscope. Structure 17(10). DOI: 10.1016/j.str.2009.09.001.
- “Team brings subatomic resolution to computational microscope” – Illinois News Bureau