Computational Methods for GPCR Drug Discovery by Alexander Heifetz

Author:Alexander Heifetz
Language: eng
Format: epub
Publisher: Springer New York, New York, NY

3 Methods

3.1 WaterFLAP MD Method

3.1.1 Coupling WaterFLAP with Molecular Dynamics

WaterFLAP allows the prediction of the location of water molecules and the evaluation of their free energy [5, 7]. It is based on GRID [10] a software to probe a protein binding site using a range of different functional groups, including water, to identify areas of attraction (hotspots). The water probe is used to detect favorable locations for water molecules in a ligand-protein complex. The energy of the waters is then evaluated combing different probes: OH2 to evaluate the hydrophilic character of the pocket, CRY (a combination of DRY and the carbon sp2 C1 = probe) to evaluate its hydrophobic/apolar components. Positional entropy of waters is estimated evaluating the energy landscape around its location. Trapped (low entropy) water molecules are located in a deep and narrow energy well, while bulk-like (high entropy) waters correspond to shallow energy basins. Since GRID is based on a united-atom force field , we introduced a short molecular dynamics step to generate an all-atoms system including a hydrogen bond network useful to understand the water network role in the stability of ligand docked poses.

The final protocol called HepWaterFlap .py is an easy-to-use python script requiring as input a protein and a docked ligand. It consists of three steps:1.Calculation of the water network using WaterFLAP (apo or protein ligand complex).

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