Understanding biology and disease requires a full connection from molecular scales, at which the fundamental biochemistry takes place, to cellular scales, where biological function (or dysfunction) is realized. Structural and molecular biology have long-focused on the molecular levels whereas systems biology emphasizes the cellular scale. The key challenge is now how to connect between these scales to gain a comprehensive understanding of complex diseases and pave the way to rational drug design at the whole-cell level. Computer simulations play a key role in this effort as they allow the modeling of biomolecules at different scales and the subsequent study of their dynamics to connect structure with function. The Feig lab focuses on the development and application of molecular dynamics and multi- scale methods for the high-resolution modeling of proteins and nucleic acids, the mechanistic analysis of fundamental biological processes such as transcription and DNA repair, and studies of biomolecules under crowded cellular environments. Future research focuses on improving protein structure refinement methods to achieve near-experimental accuracy, either de novo or in combination with high-resolution cryo EM data, improve the prediction of membrane protein structures, and develop methods for the high- resolution modeling of chromosomal DNA using experimental restraints from Hi-C data. Mechanistic studies of transcription by RNA polymerase and DNA mismatch repair initiation by MutS will be expanded to more realistic biological contexts and studies of crowded cellular environments will be continued to understand how single molecule dynamics and function is affected by the cellular environment. Finally, multi-scale methods that can bridge from molecular to cellular scales will be developed and implemented in community software.
A detailed molecular-level view of biological processes is essential for understanding the fundamental basis of disease and to develop targets for therapeutic intervention. The connection to cellular scales reaches the level where disease is manifested. This research connects molecular to cellular scales to gain a more comprehensive view of diseases that is especially relevant for highly complex diseases such as cancer.
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| Dutagaci, Bercem; Heo, Lim; Feig, Michael (2018) Structure refinement of membrane proteins via molecular dynamics simulations. Proteins 86:738-750 |
| Nawrocki, Grzegorz; Karaboga, Alp; Sugita, Yuji et al. (2018) Effect of protein-protein interactions and solvent viscosity on the rotational diffusion of proteins in crowded environments. Phys Chem Chem Phys : |
| Yildirim, Asli; Brenner, Nathalie; Sutherland, Robert et al. (2018) Role of protein interactions in stabilizing canonical DNA features in simulations of DNA in crowded environments. BMC Biophys 11:8 |
| Brocke, Stephanie; Degen, Alexandra; MacKerell, Alexander D et al. (2018) Prediction of Membrane Permeation of Drug Molecules by Combining an Implicit Membrane Model with Machine Learning. J Chem Inf Model : |
