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Characterizing loop dynamics and ligand recognition in human- and avian-type influenza neuraminidases via generalized born molecular dynamics and end-point free energy calculations.

Amaro RE, Cheng X, Ivanov I, Xu D, McCammon JA - J. Am. Chem. Soc. (2009)

Bottom Line: The enhanced sampling obtained through the implicit solvent treatment suggests several provocative insights into the dynamics of the two subtypes, including that the group-2 enzymes may exhibit similar motion in the 430-binding site regions but different 150-loop motion.End-point free energy calculations elucidate the contributions to inhibitor binding free energies and suggest that entropic considerations cannot be neglected when comparing across the subtypes.We anticipate the findings presented here will have broad implications for the development of novel antiviral compounds against both seasonal and pandemic influenza strains.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry & Biochemistry, Center for Theoretical Biological Physics, University of California, San Diego, La Jolla, California 92093-0365, USA. ramaro@mccammon.ucsd.edu

ABSTRACT
The comparative dynamics and inhibitor binding free energies of group-1 and group-2 pathogenic influenza A subtype neuraminidase (NA) enzymes are of fundamental biological interest and relevant to structure-based drug design studies for antiviral compounds. In this work, we present seven generalized Born molecular dynamics simulations of avian (N1)- and human (N9)-type NAs in order to probe the comparative flexibility of the two subtypes, both with and without the inhibitor oseltamivir bound. The enhanced sampling obtained through the implicit solvent treatment suggests several provocative insights into the dynamics of the two subtypes, including that the group-2 enzymes may exhibit similar motion in the 430-binding site regions but different 150-loop motion. End-point free energy calculations elucidate the contributions to inhibitor binding free energies and suggest that entropic considerations cannot be neglected when comparing across the subtypes. We anticipate the findings presented here will have broad implications for the development of novel antiviral compounds against both seasonal and pandemic influenza strains.

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Related in: MedlinePlus

Equilibrium orientations of oseltamivir in the different binding sites. Overall orientations (left panel) and active-site interactions (right panel) of oseltamivir bound to (a) the N1-closed, (b) the N1-open, and (c) the N9-closed system. The original conformations of the 150- and 430-loops are shown in blue and red, respectively, to highlight the loop motion observed in the course of the dynamics. Active-site residues within 4 Å of oseltamivir are shown explicitly. The original conformation of oseltamivir is shown in violet for comparison.
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fig2: Equilibrium orientations of oseltamivir in the different binding sites. Overall orientations (left panel) and active-site interactions (right panel) of oseltamivir bound to (a) the N1-closed, (b) the N1-open, and (c) the N9-closed system. The original conformations of the 150- and 430-loops are shown in blue and red, respectively, to highlight the loop motion observed in the course of the dynamics. Active-site residues within 4 Å of oseltamivir are shown explicitly. The original conformation of oseltamivir is shown in violet for comparison.

Mentions: Our analysis again reveals several interesting features of N1 vs N9 dynamics. Most notably, with the exception of Y406, all the hot-spot residues lining the sialic acid cavity in N9 exhibit much lower RMSF values than the same residues in the N1 strain (Table 3). This is also illustrated in the equilibrium binding poses of oseltamivir, which, in the N9 subtype, undergoes the least amount of movement from the original crystal structure pose versus the N1 subtypes (Figure 2). The increased positional fluctuations of the sialic acid binding residues in the N1 subtype may contribute to the reduced efficacy of several known inhibitors against N1.36,37 In addition, the N9h system shows significant stabilization of the 150-loop upon binding of oseltamivir (Table 3). The increased rigidity in this area substantiates available crystallographic data that, to date, have not provided evidence of 150-loop mobility in the N9 subtype.


Characterizing loop dynamics and ligand recognition in human- and avian-type influenza neuraminidases via generalized born molecular dynamics and end-point free energy calculations.

Amaro RE, Cheng X, Ivanov I, Xu D, McCammon JA - J. Am. Chem. Soc. (2009)

Equilibrium orientations of oseltamivir in the different binding sites. Overall orientations (left panel) and active-site interactions (right panel) of oseltamivir bound to (a) the N1-closed, (b) the N1-open, and (c) the N9-closed system. The original conformations of the 150- and 430-loops are shown in blue and red, respectively, to highlight the loop motion observed in the course of the dynamics. Active-site residues within 4 Å of oseltamivir are shown explicitly. The original conformation of oseltamivir is shown in violet for comparison.
© Copyright Policy - open-access - ccc-price
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2665887&req=5

fig2: Equilibrium orientations of oseltamivir in the different binding sites. Overall orientations (left panel) and active-site interactions (right panel) of oseltamivir bound to (a) the N1-closed, (b) the N1-open, and (c) the N9-closed system. The original conformations of the 150- and 430-loops are shown in blue and red, respectively, to highlight the loop motion observed in the course of the dynamics. Active-site residues within 4 Å of oseltamivir are shown explicitly. The original conformation of oseltamivir is shown in violet for comparison.
Mentions: Our analysis again reveals several interesting features of N1 vs N9 dynamics. Most notably, with the exception of Y406, all the hot-spot residues lining the sialic acid cavity in N9 exhibit much lower RMSF values than the same residues in the N1 strain (Table 3). This is also illustrated in the equilibrium binding poses of oseltamivir, which, in the N9 subtype, undergoes the least amount of movement from the original crystal structure pose versus the N1 subtypes (Figure 2). The increased positional fluctuations of the sialic acid binding residues in the N1 subtype may contribute to the reduced efficacy of several known inhibitors against N1.36,37 In addition, the N9h system shows significant stabilization of the 150-loop upon binding of oseltamivir (Table 3). The increased rigidity in this area substantiates available crystallographic data that, to date, have not provided evidence of 150-loop mobility in the N9 subtype.

Bottom Line: The enhanced sampling obtained through the implicit solvent treatment suggests several provocative insights into the dynamics of the two subtypes, including that the group-2 enzymes may exhibit similar motion in the 430-binding site regions but different 150-loop motion.End-point free energy calculations elucidate the contributions to inhibitor binding free energies and suggest that entropic considerations cannot be neglected when comparing across the subtypes.We anticipate the findings presented here will have broad implications for the development of novel antiviral compounds against both seasonal and pandemic influenza strains.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry & Biochemistry, Center for Theoretical Biological Physics, University of California, San Diego, La Jolla, California 92093-0365, USA. ramaro@mccammon.ucsd.edu

ABSTRACT
The comparative dynamics and inhibitor binding free energies of group-1 and group-2 pathogenic influenza A subtype neuraminidase (NA) enzymes are of fundamental biological interest and relevant to structure-based drug design studies for antiviral compounds. In this work, we present seven generalized Born molecular dynamics simulations of avian (N1)- and human (N9)-type NAs in order to probe the comparative flexibility of the two subtypes, both with and without the inhibitor oseltamivir bound. The enhanced sampling obtained through the implicit solvent treatment suggests several provocative insights into the dynamics of the two subtypes, including that the group-2 enzymes may exhibit similar motion in the 430-binding site regions but different 150-loop motion. End-point free energy calculations elucidate the contributions to inhibitor binding free energies and suggest that entropic considerations cannot be neglected when comparing across the subtypes. We anticipate the findings presented here will have broad implications for the development of novel antiviral compounds against both seasonal and pandemic influenza strains.

Show MeSH
Related in: MedlinePlus