Olaf Wiest

Professor of Chemistry & Biochemistry


305E McCourtney Hall

Research Cluster

Computational Models, Dynamics & Reactions

Computational Biophysics

The detailed understanding of enzyme-catalyzed reactions is of paramount importance in biophysical chemistry. In addition to the basic scientific aspect of understanding the world around us, this understanding is important for the development of drugs and chemical tools to modulate biological systems and disease processes. Computational methods are unique tools in the study of biomolecules because they can combine information from many areas to generate atomic-level, physics-based models that include structural, dynamic and energetic information.

We use a wide range of computational methods including electronic structure methods, molecular dynamics, docking and bioinformatics as well as the Quantum Guided Molecular Mechanics (Q2MM) method developed in our group to study the structure,dynamics, and reactivity of proteins and to design bioactive modulators of their activity.The models and designed molecules are then tested experimentally either in our laboratories or by our collaborators. Some recent projects include:

  • Development of the Q2MM program to automatically generate transition state force field (TSFF) parameters for computational enzymology
  • The complete mechanism of HMGCoA Reductase in atomistic detail using time resolved Laue crystallography and TSFFs
  • Identification of p. falciparum PI3K as the target of artemisinin in malaria, which is used in the design and optimization of new pfPI3K inhibitors
  • Structural origin of isoform selectivity in HDAC and bromodomain inhibitors
  • Development and clinical study of HDAC inhibitors for the treatment of Niemann-Pick type C disease


  1. "Prediction of Stereochemistry using Q2MM" Hansen, E.; Rosales, A.R.; Tutkowski, B.M.; Norrby, P.O.; Wiest, O. Acc. Chem. Res. 2016, 49, 996-1005.
  2. "A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria" Mbengu, A.; Bhattacharjee, S.; Pandharkar, T.; Liu, H.; Estiu, G.; Stahelin, R.V.; Rizk, S.; Njimoh, D.L.; Ryan, Y.; Chotivanich, K.; Nguon, C.; Ghorbal, M.; Lopez-Rubio, J.-J.; Pfrender, M.; Emrich, S.; Mohandas, N.; Dondorp, A.M.; Wiest, O.; Haldar, K. Nature 2015, 520, 683-687.
  3. "Inhibition and Mechanism of HDAC8 Revisited" Chen, K.; Zhang, X.; Wu, Y.D.; Wiest, O. J. Am. Chem. Soc. 2014, 136, 11636-11643.
  4. "The Increasingly Complex Mechanism of HMG-CoA Reductase" Acc. Chem. Res. 2013, 46, 2416-2426.