New Combination of Force Fields for Modeling Large Enzymes


Roy, Indu


Indu Sekhar Roy

Model-Based Fuel Design


+49 241 80 95354



In-depth knowledge of enzyme kinetics is essential for the design and optimization of drugs as well as for protein engineering. For example, "A Disintegrin and Metalloproteinase" (ADAM) is a family of transmembrane enzymes that affect the communication among cells. ADAM10 and 17 from this family, which are very important for the regeneration of tissue, are novel pharmaceutical targets for lung inflammation. Knowledge about exact shedding mechanism of full-length ADAM 10/17 molecules is interesting because inhibition of shedding may provide a novel therapeutic approach for treating cancers. Precise inspections of the catalytic mechanism through experiments alone is not possible. This can be studied only through computational methods with molecular-level modeling.

  New Combination of Force Fields for Modeling Large Enzymes

In the state-of-art method, the reactive part of an enzyme is modeled through computational quantum mechanics (QM) methods such as Density Functional Theory (DFT), which can accurately estimate the catalysis reaction, while the faster non-reactive molecular mechanics (MM) describes rest of the system. This approach is famously known as Nobel Prize awarded QM/MM molecular simulation [2]. However, QM is highly computationally expensive. For the best case scenario, the order of complexity is O (N 3), where N is the number of atoms. Explicitly, if the size of the system doubles, the computational cost increases by the factor of 8. The simulation of very large scale enzymes with this method is impractical. Thus, a reduced-order computational model is indispensable to analyze the enzyme catalysis.


Molecular dynamics simulations with an empirical force field are faster in computation with the cost of accuracy. In practice, molecular simulations with non-reactive force fields are very fast in computation and they can model the structure and the dynamics but cannot reproduce either the catalytic activity or other reaction mechanisms. On the other hand, a reactive force field, e.g. ReaxFF [3], can model the breaking and forming of bonds and thereby can describe the chemical reactions and catalytic activities. In this project, various kinds of force field will be investigated simultaneously to model the reaction kinetics of large enzymes like ADAM 10/17 towards the goal of better modeling of pharmaceutical substances and eradicating detrimental side effects.



[1] R. Lonsdale, J.N. Harvey, A.J. Mulholland. A practical guide to modelling enzyme-catalysed reactions. Chemical Society Reviews, 41:3025-3038, 2012.

[2] A. Warshel. Multiscale modeling of biological functions: from enzymes to molecular machines (Nobel Lecture). Angewandte Chemie International Edition, 53:10020- 10031, 2014.

[3] A.C.T. van Duin, S. Dasgupta, F. Lorant, et al. ReaxFF: a reactive force field for hydrocarbons. The Journal of Physical Chemistry A, 41:9396–9409, 2001.


Project Details

Project duration

3 Years


AICES - Aachen Institute for Advanced Study in Computational Engineering Science