back to AG Gohlke

Expertise in Structural Biology

Structural and molecular bioinformatics
Molecular dynamics simulations
Free energy calculations

The goal of structural and molecular bioinformatics is to make use of available high-resolution structural information about biological systems to reason about their respective function and to predict the effects of modifications or perturbations. Within the field, methods are being developed that aim at I) building structural models from components (“docking”), II) creating improved or new functionalities of biomacromolecules (“protein engineering”, “enzyme design”), III) rationally designing drugs (“structure-based drug design”), and IV) simulating structural models for gaining insight into the relation between structure and function. As for the last, biomolecules are not rigid structures, as implied by structural models of their three-dimensional architecture. Rather, they are dynamic systems, whose internal dynamics play a fundamental role for function. Molecular dynamics (MD) simulations provide an important tool for understanding the physical basis of biomacromolecular structure and function. In particular, MD simulations can provide detailed insights with respect to motions of single atoms as a function of time. This leads to three main types of applications of MD simulations: I) sampling configuration space, e.g., for predicting or refining biomacromolecular structures; II) obtaining information about the biomacromolecular system at equilibrium, i.e., determining structural and motional properties as well as thermodynamic quantities, such as (binding) free energies; III) examining the actual dynamics, e.g., for helping in interpreting NMR and other spectroscopic data. Continuing developments in simulation methodologies and advances in computer speed have allowed extending MD simulations to molecular machines (e.g., the ribosome or ATP synthase), longer time scales on the order of microseconds, and greater conformational changes. Based on advances in imaging and fluorescent labelling techniques, which give insights into the location and dynamics of biomacromolecules in cells, the next challenge for simulation techniques is to go beyond the (supra-)molecular level towards the level of organelles and cells.

Figure Legend:
I: Superimposition of open (blue) and closed (green) conformations of adenylate kinase. In addition, the amplitudes and directions of motions as predicted by a rigid cluster normal mode analysis are depicted as red arrows. See also Proteins 2006, 63, 1038-1051.
II: Averaged structure from a MD simulation of a double strand RNA containing a central self-pair of 2,4-difluorobenzene bases. Substructural free energy contributions to the relative binding free energy with respect to a 4-fluorobenzene self-pair are color-coded. See also ChemBioChem 2008, 9, 2619-2622.
III: Comparing the rigidity and flexibility within a protein constraint network before (a) and after (b) a phase transition allows characterizing structural features in atomic detail that determine the stability of a protein structure (red arrows). See also Eng. Life Science 2008, 8, 507-522.