High-fidelity Biomolecular Modelling
Although molecular dynamics (MD) simulations are a widely used tool in (bio)sciences, they often actually fail to provide a veritable description (e.g. matching NMR data within experimental accuracy) of the conformations and the dynamics of the molecules simulated—a crucial prerequisite for using MD to intuitively interpret such high-resolution experiments. These failures can largely be attributed to the quality of the underlying MD models (force fields), improvement of which is hindered by the lack of comprehensive comparison to experiments, and outdated approaches, such as hand-tuning parameters. The High-fidelity Biomolecular Modelling Group employs open-science approaches to test and data-driven optimization methods to improve biomolecular force fields. We strive to make such force-field-optimized MD a tool for Integrative Structural Biology: Combining data from multiple experimental techniques to generate physics-based high-fidelity structural models with realistic structure and dynamics. I argue that such approach could eventually evolve MD into a bona fide Ångström-resolution microscope.
How do you turn convoluted NMR signals into a comprehensible picture of moving molecules? The answer is “autofocus” in molecular dynamics: systematic fine-tuning of simulations so that they faithfully mirror the experiment. The result is credible 3D videos with sub-nanometer spatial and sub-nanosecond temporal resolution. This year's Nobel Prize in Chemistry highlighted a breakthrough in predicting protein structures: from the amino acid sequence we can obtain a very accurate “static” shape. But living systems are not motionless – molecules are constantly moving and changing conformations. The key question therefore is: how do we get from a fixed structure to realistic motions? NMR provides extremely precise information about local motions of atoms, but the signal resembles a “zoo of peaks” that cannot be reliably deciphered by eye alone. Molecular dynamics (MD), in turn, shows how molecules move over time, but standard simulations may not reproduce the data. It is their combination where the magic can be turned into a tool.From static models to living biology
