PROSA: PROtein Simulated Annealing

For detailed modeling and docking, it is necessary to calculate the hydrogen atom positions of protein structures obtained by X-ray crystallography. Residues with polar hydrogens and structural water molecules can often form intricate hydrogen bond patterns (Figure 1). Uncovering these requires the simultaneous molecular mechanics energy optimization of all polar hydrogen atom positions. This has to be performed with a global optimization algorithm to avoid getting trapped in local, non-optimal energy minima. We have developed a simulated annealing based algorithm that adjusts the orientation and position of water molecules, the torsional position of hydroxyl, sulfhydryl and amino hydrogens of Tyr, Thr, Ser, Cys, and Lys, and the acid groups of Asp and Gly, to minimize the total molecular mechanics energy of a protein structure.


hydrogen bond network in influenza neuraminidase
Figure 1: hydrogen bond pattern in the binding site of Influenza Neuraminidase with inhibitor.

Figure 2 illustrates the energy evolution during the optimization of the catalytic center of the C-ABL kinase domain in complex with imatinib (PDB entry 1IEP) containing 34 water atoms, 12 acid groups, 14 lysines and 10 hydroxy and sulfhydryl rotors.


internal energy reduction of the 1IEP hydrogen bond network
Figure 2: Evolution of the average energy (green) and lowest energy (red during the PROSA simulated annealing optimization of hydrogen atom orientations.