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Biomolecular Simulation and Modeling

research

People involved:
Staf: Daan P. Geerke, Nico P.E. Vermeulen
Senior scientist: Marc van Dijk
PhD students: Rosa A. Luirink, Koen M. Visscher, Eko A. Rifai

Research activities:

Our computational research (currently funded by a NLeSC-ASDI eScience grant and a NWO-VIdi grant of Geerke, and previously by the IMI-JU eTOX project) focuses on developing and improving in silico models to study proteins and other biomolecules in simulation, and on understanding ligand-protein interactions at the atomistic level of detail. By using and developing new molecular dynamics-based methods, ligand-affinities and selectivities are predicted and trends in binding and experimental results are studied and rationalized. Recent awareness that protein plasticity plays a crucial role in Cytochrome P450 (CYP) activities lends urgency to our research lines to take induced fit effects and protein dynamics into account in a more accurate and efficient manner. For the first time, we were thus able to use the conformations derived from the CYP 2D6 crystal structure for the prediction of substrate binding orientations. A next step will be to develop methods to accurately ànd efficiently predict binding affinities to and selectivities of relevant CYP isoforms and other (flexible) proteins.

We are also involved in biocatalytic research within our Division that aims on developing highly active and selective drug-metabolizing mutants of bacterial Cytochrome P450 BM3 (CYP102A1). For this purpose, the structural basis for the increase in (regio- and stereo-) selectivity in e.g. steroid and food-additive metabolism and in generation of biomarkers was recently successfully elucidated, which has directed identification of mutants capable of selective substrate hydroxylation at positions that were not observed before for BM3.

In parallel, our force fields (classical potential-energy models) are being revised in order to more accurately describe protein-ligand interactions in simulation, by introducing electronic polarization effects as a next level of theory. This research has been funded in the context of a NWO-Veni grant.

Key publications:

Verhoef D, Visscher KM, Vosmeer CR, Cheung KL, Reistma PH, Geerke DP, Bos MHA. "Engineered Factor Xa variants retain procoagulent activity independent of direct Factor Xa inhibitors." Nature Commun. 2017, accepted.

van Dijk M, ter Laak AM, Wichard JD, Capoferri L, Vermeulen NPE, Geerke DP. "Comprehensive and Automated Linear Interaction Energy Based Binding Affinity Prediction for Multifarious Cytochrome P450 Aromatase Inhibitors." J. Chem. Inf. Model. 2017, just accepted. DOI: 10.1021/acs.jcim.7b00222

Visscher KM, Vosmeer CR, Luirink RA, Geerke DP. "A Systematic Approach to Calibrate a Transferable Polarizable Force Field Parameter Set for Primary Alcohols." J. Comput. Chem. 2017, 38, 508-517

Capoferri L, Leth R, ter Haar E, Mohanty AK, Grootenhuis PDJ, Vottero E, Commandeur JNM, Vermeulen NPE, Jørgensen FS, Olsen L, Geerke DP. "Insights into regioselective metabolism of mefenamic acid by cytochrome P450 BM3 mutants through crystallography, docking, molecular dynamics, and free energy calculations." Proteins 2016, 84, 383-396.

Capoferri L,Verkade-Vreeker MCA, Buitenhuis D, Commandeur JNM, Pastor M, Vermeulen NPE, Geerke DP. "Linear Interaction Energy Based Prediction of Cytochrome P450 1A2 Binding Affinities with Reliability Estimation." PLOS ONE 2015, 10, e0142232

Vosmeer CR, Pool R, van Stee MF, Peric-Hassler L, Vermeulen NPE, Geerke DP: "Towards automated binding affinity prediction using an iterative linear interaction energy approach." Int. J. Mol. Sc. 2014, 15, 798-816

Vosmeer CR, Rustenburg AS, Rice JE, Horn HW, Swope WC,Geerke DP: "QM/MM-Based Fitting of Atomic Polarizabilities for Use in Condensed-Phase Biomolecular Simulation." J. Chem. Theory Comput. 2012, 8, 3839-3853.