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Analysis of factors influencing hydration site prediction based on molecular dynamics simulations.

Yang Y, Hu B, Lill MA - J Chem Inf Model (2014)

Bottom Line: Water contributes significantly to the binding of small molecules to proteins in biochemical systems.However, questions associated with the influence of the simulation protocol on hydration site analysis remain.Here, we provide a first quantification of this effect and further indicate that similar conformations of binding site residues (RMSD < 0.5 Å) are required to obtain consistent hydration site predictions.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University , 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.

ABSTRACT
Water contributes significantly to the binding of small molecules to proteins in biochemical systems. Molecular dynamics (MD) simulation based programs such as WaterMap and WATsite have been used to probe the locations and thermodynamic properties of hydration sites at the surface or in the binding site of proteins generating important information for structure-based drug design. However, questions associated with the influence of the simulation protocol on hydration site analysis remain. In this study, we use WATsite to investigate the influence of factors such as simulation length and variations in initial protein conformations on hydration site prediction. We find that 4 ns MD simulation is appropriate to obtain a reliable prediction of the locations and thermodynamic properties of hydration sites. In addition, hydration site prediction can be largely affected by the initial protein conformations used for MD simulations. Here, we provide a first quantification of this effect and further indicate that similar conformations of binding site residues (RMSD < 0.5 Å) are required to obtain consistent hydration site predictions.

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Percentage of paired hydration sites out ofall predicted hydrationsites found in different RMSD groups of each protein system.
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fig3: Percentage of paired hydration sites out ofall predicted hydrationsites found in different RMSD groups of each protein system.

Mentions: To quantitatively analyze how similar the hydration sites are predictedin each RMSD group, pairwise hydration site comparisons were carriedout within each RMSD group, resulting in 10 pairwise comparisons perRMSD group. For each comparison, we identified paired hydration sitesand calculated the percentage of paired hydration sites from all predictedhydration sites. This distribution of paired hydration sites for allfour protein systems is displayed in the form of a boxplot graph foreach RMSD group in Figure 3. As expected, morepaired hydration sites were found in the group with smaller conformationalvariation than those with larger initial RMSD. On average more than80% of all hydration sites have similar locations when the startingprotein structures are very similar (RMSD 0–0.5 Å), whileonly about a third of the hydration sites have similar locations ifthe starting structures deviate by 1–1.5 Å RMSD. Thisdemonstrates the high sensitivity of WATsite and likely other MD-basedhydration site programs on the starting protein structure.


Analysis of factors influencing hydration site prediction based on molecular dynamics simulations.

Yang Y, Hu B, Lill MA - J Chem Inf Model (2014)

Percentage of paired hydration sites out ofall predicted hydrationsites found in different RMSD groups of each protein system.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4210176&req=5

fig3: Percentage of paired hydration sites out ofall predicted hydrationsites found in different RMSD groups of each protein system.
Mentions: To quantitatively analyze how similar the hydration sites are predictedin each RMSD group, pairwise hydration site comparisons were carriedout within each RMSD group, resulting in 10 pairwise comparisons perRMSD group. For each comparison, we identified paired hydration sitesand calculated the percentage of paired hydration sites from all predictedhydration sites. This distribution of paired hydration sites for allfour protein systems is displayed in the form of a boxplot graph foreach RMSD group in Figure 3. As expected, morepaired hydration sites were found in the group with smaller conformationalvariation than those with larger initial RMSD. On average more than80% of all hydration sites have similar locations when the startingprotein structures are very similar (RMSD 0–0.5 Å), whileonly about a third of the hydration sites have similar locations ifthe starting structures deviate by 1–1.5 Å RMSD. Thisdemonstrates the high sensitivity of WATsite and likely other MD-basedhydration site programs on the starting protein structure.

Bottom Line: Water contributes significantly to the binding of small molecules to proteins in biochemical systems.However, questions associated with the influence of the simulation protocol on hydration site analysis remain.Here, we provide a first quantification of this effect and further indicate that similar conformations of binding site residues (RMSD < 0.5 Å) are required to obtain consistent hydration site predictions.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University , 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.

ABSTRACT
Water contributes significantly to the binding of small molecules to proteins in biochemical systems. Molecular dynamics (MD) simulation based programs such as WaterMap and WATsite have been used to probe the locations and thermodynamic properties of hydration sites at the surface or in the binding site of proteins generating important information for structure-based drug design. However, questions associated with the influence of the simulation protocol on hydration site analysis remain. In this study, we use WATsite to investigate the influence of factors such as simulation length and variations in initial protein conformations on hydration site prediction. We find that 4 ns MD simulation is appropriate to obtain a reliable prediction of the locations and thermodynamic properties of hydration sites. In addition, hydration site prediction can be largely affected by the initial protein conformations used for MD simulations. Here, we provide a first quantification of this effect and further indicate that similar conformations of binding site residues (RMSD < 0.5 Å) are required to obtain consistent hydration site predictions.

Show MeSH