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Insights into the dynamics of HIV-1 protease: a kinetic network model constructed from atomistic simulations.

ABSTRACT: The conformational dynamics in the flaps of HIV-1 protease plays a crucial role in the mechanism of substrate binding. We develop a kinetic network model, constructed from detailed atomistic simulations, to determine the kinetic mechanisms of the conformational transitions in HIV-1 PR. To overcome the time scale limitation of conventional molecular dynamics (MD) simulations, our method combines replica exchange MD with transition path theory (TPT) to study the diversity and temperature dependence of the pathways connecting functionally important states of the protease. At low temperatures the large-scale flap opening is dominated by a small number of paths; at elevated temperatures the transition occurs through many structurally heterogeneous routes. The expanded conformation in the crystal structure 1TW7 is found to closely mimic a key intermediate in the flap-opening pathways at low temperature. We investigated the different transition mechanisms between the semi-open and closed forms. The calculated relaxation times reveal fast semi-open ? closed transitions, and infrequently the flaps fully open. The ligand binding rate predicted from this kinetic model increases by 38-fold from 285 to 309 K, which is in general agreement with experiments. To our knowledge, this is the first application of a network model constructed from atomistic simulations together with TPT to analyze conformational changes between different functional states of a natively folded protein.

SUBMITTER: Deng NJ

PROVIDER: S-EPMC3116037 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Insights into the dynamics of HIV-1 protease: a kinetic network model constructed from atomistic simulations.

Deng Nan-jie NJ Zheng Weihua W Gallicchio Emillio E Levy Ronald M RM

Journal of the American Chemical Society 20110525 24

The conformational dynamics in the flaps of HIV-1 protease plays a crucial role in the mechanism of substrate binding. We develop a kinetic network model, constructed from detailed atomistic simulations, to determine the kinetic mechanisms of the conformational transitions in HIV-1 PR. To overcome the time scale limitation of conventional molecular dynamics (MD) simulations, our method combines replica exchange MD with transition path theory (TPT) to study the diversity and temperature dependenc ...[more]

PMID: 21561098

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Project description:The hillslope and channel dynamics that govern streamflow permanence in headwater systems have important implications for ecosystem functioning and downstream water quality. Recent advancements in process-based, semi-distributed hydrologic models that build upon empirical studies of streamflow permanence in well-monitored headwater catchments show promise for characterizing the dynamics of streamflow permanence in headwater systems. However, few process-based models consider the continuum of hillslope-stream network connectivity as a control on streamflow permanence in headwater systems. The objective of this study was to expand a process-based, catchment-scale hydrologic model to better understand the spatiotemporal dynamics of headwater streamflow permanence and to identify controls of streamflow expansion and contraction in a headwater network. Further, we aimed to develop an approach that enhanced the fidelity of model simulations, yet required little additional data, with the intent that the model might be later transferred to catchments with limited long-term and spatially explicit measurements. This approach facilitated network-scale estimates of the controls of streamflow expansion and contraction, albeit with higher degrees of uncertainty in individual reaches due to data constraints. Our model simulated that streamflow permanence was highly dynamic in first-order reaches with steep slopes and variable contributing areas. The simulated stream network length ranged from nearly 98±2% of the geomorphic channel extent during wet periods to nearly 50±10% during dry periods. The model identified a discharge threshold of approximately 1 mm d-1, above which the rate of streamflow expansion decreases by nearly an order of magnitude, indicating a lack of sensitivity of streamflow expansion to hydrologic forcing during high-flow periods. Overall, we demonstrate that process-based, catchment-scale models offer important insights on the controls of streamflow permanence, despite uncertainties and limitations of the model. We encourage researchers to increase data collection efforts and develop benchmarks to better evaluate such models.

Dataset Information

Insights into the dynamics of HIV-1 protease: a kinetic network model constructed from atomistic simulations.

Publications

Insights into the dynamics of HIV-1 protease: a kinetic network model constructed from atomistic simulations.

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