Gating and Intermolecular Interactions in Ligand-Protein Association: Coarse-Grained Modeling of HIV-1 Protease

Equilibrium constants, together with kinetic rate constants of binding, are key factors in the efficacy and safety of drug compounds, informing drug design. However, the association pathways of protein–ligand binding, which contribute to their kinetic behaviors, are little understood. In this work, we used unbiased all-atom molecular dynamics (MD) simulations with an explicit solvent model to study the association processes of protein–ligand binding. Using the HIV protease (HIVp)–xk263 and HIVp–ritonavir protein–ligand systems as cases, we observed that ligand association is a multistep process involving diffusion, localization, and conformational rearrangements of the protein, ligand, and water molecules. Moreover, these two ligands preferred different routes of binding, which reflect two well-known binding mechanisms: induced-fit and conformation selection models. Our study shows that xk263 has a stronger capacity for desolvating surrounding water molecules, thereby inducing a semiopen conformation of the HIVp flaps (induced-fit model). In contrast, the slow dehydration characteristic of ritonavir allows for gradual association with the binding pocket of HIVp when the protein’s flap conformation is fully open (conformation selection model). By studying the mechanism of ligand association and understanding the role of solvent molecules during the binding event, we can obtain a different perspective on the mechanism of macromolecule recognition, providing insights into drug discovery.

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“…From previous Brownian dynamics (BD) studies, this cutoff reflects a high probability of successful binding. 21 …”

Section: Methodsmentioning

confidence: 99%

Mechanism of the Association Pathways for a Pair of Fast and Slow Binding Ligands of HIV-1 Protease

et al. 2017

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“…In this regime, internal motions have to be explicitly modeled during the association. A few such simulation studies, on binding of small molecules to proteins, have been published over the years [27,28]. Using algorithms originally designed for calculating the association rate constants of rigid molecules [8,9] to calculate the association of flexible molecules presents the formidable challenge of having to simulate internal motions over the length of time required for achieving successful association.…”

Section: Modeling Conformational Changes During Associationmentioning

confidence: 99%

Modeling protein association mechanisms and kinetics

Zhou

Bates

2013

Current Opinion in Structural Biology

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Substantial advances have been made in modeling protein association mechanisms and in calculating association rate constants (ka). We now have a clear understanding of the physical factors underlying the wide range of experimental ka values. Half of the association problem, where ka is limited by diffusion, is perhaps solved, and for the other half, where conformational changes become rate-limiting, a number of promising methods are being developed for ka calculations. Notably, the binding kinetics of disordered proteins are receiving growing attention, with “dock-and-coalescence” emerging as a general mechanism. Progress too has been made in the modeling of protein association kinetics under conditions mimicking the heterogeneous, crowded environments of cells, an endeavor that should ultimately lead to a better understanding of cellular functions.

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“…Such models, after careful parameterization, allow both overall translational and rotational diffusion and internal conformational fluctuations to be modeled by Brownian dynamics simulations. 28 Implementation of BDflex within such more realistic models of protein-ligand systems is underway.…”

Section: Discussionmentioning

confidence: 99%

BDflex: A method for efficient treatment of molecular flexibility in calculating protein-ligand binding rate constants from Brownian dynamics simulations

Greives

Zhou

2012

The Journal of Chemical Physics

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A method developed by Northrup et al. [J. Chem. Phys. 80, 1517] for calculating proteinligand binding rate constants (k a ) from Brownian dynamics (BD) simulations has been widely used for rigid molecules. Application to flexible molecules is limited by the formidable computational cost to treat conformational fluctuations during the long BD simulations necessary for k a calculation. Here, we propose a new method called BDflex for k a calculation that circumvents this problem. The basic idea is to separate the whole space into an outer region and an inner region, and formulate k a as the product of k E andη d , which are obtained by separately solving exterior and interior problems. k E is the diffusion-controlled rate constant for the ligand in the outer region to reach the dividing surface between the outer and inner regions; in this exterior problem conformational fluctuations can be neglected.η d is the probability that the ligand, starting from the dividing surface, will react at the binding site rather than escape to infinity. The crucial step in reducing the determination ofη d to a problem confined to the inner region is a radiation boundary condition imposed on the dividing surface; the reactivity on this boundary is proportional to k E . By confining the ligand to the inner region and imposing the radiation boundary condition, we avoid multiple-crossing of the dividing surface before reaction at the binding site and hence dramatically cut down the total simulation time, making the treatment of conformational fluctuations affordable. BDflex is expected to have wide applications in problems where conformational fluctuations of the molecules are crucial for productive ligand binding, such as in cases where transient widening of a bottleneck allows the ligand to access the binding pocket, or the binding site is properly formed only after ligand entrance induces the closure of a lid.

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Gating and Intermolecular Interactions in Ligand-Protein Association: Coarse-Grained Modeling of HIV-1 Protease

Cited by 34 publications

References 55 publications

Mechanism of the Association Pathways for a Pair of Fast and Slow Binding Ligands of HIV-1 Protease

Mechanism of the Association Pathways for a Pair of Fast and Slow Binding Ligands of HIV-1 Protease

Modeling protein association mechanisms and kinetics

BDflex: A method for efficient treatment of molecular flexibility in calculating protein-ligand binding rate constants from Brownian dynamics simulations

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