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Molecular dynamics and free energy analysis of neuraminidase-ligand interactions.

ABSTRACT: We report molecular dynamics calculations of neuraminidase in complex with an inhibitor, 4-amino-2-deoxy-2,3-didehydro-N-acetylneuraminic acid (N-DANA), with subsequent free energy analysis of binding by using a combined molecular mechanics/continuum solvent model approach. A dynamical model of the complex containing an ionized Glu119 amino acid residue is found to be consistent with experimental data. Computational analysis indicates a major van der Waals component to the inhibitor-neuraminidase binding free energy. Based on the N-DANA/neuraminidase molecular dynamics trajectory, a perturbation methodology was used to predict the binding affinity of related neuraminidase inhibitors by using a force field/Poisson-Boltzmann potential. This approach, incorporating conformational search/local minimization schemes with distance-dependent dielectric or generalized Born solvent models, correctly identifies the most potent neuraminidase inhibitor. Mutation of the key ligand four-substituent to a hydrogen atom indicates no favorable binding free energy contribution of a hydroxyl group; conversely, cationic substituents form favorable electrostatic interactions with neuraminidase. Prospects for further development of the method as an analysis and rational design tool are discussed.

SUBMITTER: Bonnet P

PROVIDER: S-EPMC2280046 | biostudies-literature | 2004 Apr

REPOSITORIES: biostudies-literature

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Molecular dynamics and free energy analysis of neuraminidase-ligand interactions.

Bonnet Pascal P Bryce Richard A RA

Protein science : a publication of the Protein Society 20040401 4

We report molecular dynamics calculations of neuraminidase in complex with an inhibitor, 4-amino-2-deoxy-2,3-didehydro-N-acetylneuraminic acid (N-DANA), with subsequent free energy analysis of binding by using a combined molecular mechanics/continuum solvent model approach. A dynamical model of the complex containing an ionized Glu119 amino acid residue is found to be consistent with experimental data. Computational analysis indicates a major van der Waals component to the inhibitor-neuraminidas ...[more]

PMID: 15044728

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Project description:HIV-1 protease (HIV-1-pr) plays an important role in viral replication and maturation, making it one of the most attractive targets for anti-retroviral therapy. To design new effective inhibitors able to combat drug resistance in mutant HIV-1-pr variants, it is essential to gain further understanding about the mechanisms by which the recently proposed inhibitors deactivate the mutant HIV-1-pr variants. In the present work, we explored the interactions between two P2-ligands (DRV, and one new derivative, 4UY) with wild type (WT) and two multiple mutant HIV-1-pr variants (p20 and p51) with all atom molecular dynamics (MD) simulations, binding free energy calculations, and principal component analysis (PCA). The trajectories of MD simulations show that both 4UY and DRV primarily bind with the active sites, flap and 80s loop regions of HIV-1-pr variants through either hydrogen bonds or hydrophobic interactions. More hydrogen bonds and hydrophobic interactions were located for 4UY/HIV-1-pr complexes than for DRV/HIV-1-pr counterparts. More importantly, 4UY was found to have an extra hydrogen bond with the backbone of Gly48' in the flap region of the HIV-1-prs. The flap tip-tip distance (I50-I50') and flap tip-active site distance (I50-D25 and I50'-D25') indicate that the flaps turn more closed in 4UY bound HIV-1-prs than DRV bound ones, and the former also have more compact hydrophobic cavities than the latter. Further, the vector projections from PCA indicate that 4UY/DRV inhibitor binding projects the closing of flap in HIV-1-pr variants. In line with the above trajectory analysis, the thermodynamics calculation with MM-PBSA method suggests much stronger binding affinity for 4UY/HIV-1-pr than DRV/HIV-1-pr by 4.3-6.4 kcal/mol. Although p20 and p51 also induce weaker binding due to multiple mutants for 4UY inhibitor by 1.9-1.8 kcal/mol, their bindings to the new P2 ligand (4UY) are indeed significantly enhanced as compared to DRV. The thermodynamic components responsible for the binding differences and the contribution from key residues to the binding were also discussed in detail.

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Molecular dynamics and free energy analysis of neuraminidase-ligand interactions.

Publications

Molecular dynamics and free energy analysis of neuraminidase-ligand interactions.

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