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| About Marc Nicklaus (National Institutes of Health) |
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Dr. Marc Nicklaus received his Ph.D. in applied physics from the Eberhards-Karls-Universität, Tübingen, Germany, in 1989. He served as a postdoctoral fellow in the Molecular Modeling Section of the Laboratory of Medicinal Chemistry (LMC), NCI, NIH, and subsequently became staff fellow in 1998 and Senior Scientist in 2002. He has been heading the newly founded Computer-Aided Drug Design Group of the LMC since 2000.
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High Quantum-chemical Ligand Energies - True Binding Effects or Crystallographic Artifacts?
Marc Nicklaus, National Institutes Health
We analyzed conformational changes of ligands binding to proteins in an early paper in the field (Nicklaus et al., Bioorg. Med. Chem. 3, 411-428, 1995). Both geometric and energetic aspects were studied. Surprisingly high conformational energies relative to the vacuum global energy minimum were found for some ligands. The question of such high ligand energies is still discussed controversially to this day. The previous study was necessarily limited by methodology due mainly to availability of computing power, and by number of structures due to historically much smaller database sizes. To improve on this analysis in all aspects possible, and to attempt to provide a more definitive answer to the possibility of high ligand conformational energies, a new effort is being undertaken to analyze ligand energies. To this purpose, a high-quality subset of all ligand occurrences (individual 3D coordinate sets) in the Protein Data Bank (PDB) has been compiled by filtering the entire PDB ligand database by crystallographic resolution, average ligand B-factor, true ligand nature and other criteria. Structures from this subset are then submitted to high-level quantum chemical calculations using the program Gaussian 03 to obtain energies in step-wise optimization of first bond lengths, then bond angles, and finally dihedrals. These energies are compared to the energy of global energy minimum structures obtained in molecular mechanics force field approaches, fully re-optimized at the quantum chemical level. Typical levels of theory used are Density Functional Theory (DFT) computations using B3LYP/6-31G(d) for optimizations, B3LYP/6-311++G(3df,2p) for single-point calculations. An attempt is made to discuss the obtained results as to the possibility of distinguishing whether high-energy conformations of ligands found in the PDB are true characteristics of protein-ligand complexes or artifacts introduced in one of the many steps from growing the crystal to deposition of the coordinates in the PDB.
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