Flap opening mechanism of HIV-1 protease

Tóth, Gergely; Borics, Attila

doi:10.1016/j.jmgm.2005.08.008

Cited by 69 publications

(96 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Another report [37] used molecular dynamics constrained to dihedral angle space to speed up the sampling. The authors observed transitions between semi-open and open conformations, although the semi-open structure following the opening event did not show close agreement with the crystallographic form, which might have resulted from simplifications used in internal coordinate space dynamics.…”

Section: Simulations Of Hiv-1 Protease: Exploring Flap Flexibilitymentioning

confidence: 99%

Targeting structural flexibility in HIV-1 protease inhibitor binding

Horn̆ák

Simmerling

2007

Drug Discovery Today

108

104

View full text Add to dashboard Cite

SummaryHIV-1 protease remains an important AIDS drug target. Even though it has been known that ligand binding induces large conformational changes in the protease, the dynamic aspects of binding have been largely ignored. Several computational models describing protease dynamics have been reported recently. These have reproduced experimental observations, and also explained how ligands gain access to the binding site through dynamic behavior of the protease. Specifically, the transitions between three different conformations of the protein have been modeled in atomic detail. Two of these forms were determined by crystallography, the third one was implied by NMR experiments. Based on these computational models, it has been suggested that binding of inhibitors in allosteric sites may affect protease flexibility and disrupt its function.

show abstract

Section: Simulations Of Hiv-1 Protease: Exploring Flap Flexibilitymentioning

confidence: 99%

Targeting structural flexibility in HIV-1 protease inhibitor binding

Horn̆ák

Simmerling

2007

Drug Discovery Today

108

104

View full text Add to dashboard Cite

show abstract

“…Flaps have been shown to regulate entry to the active site of proteases by providing access for substrate and/or inhibitors binding (15,18). Flap opening and closure in HIV protease (16) have been well studied using molecular dynamics (16,(19)(20)(21)(22)(23)(24)(25)(26). In general, different parameters have been proposed to describe the flap motion in the case of the HIV protease (20).…”

Section: Introductionmentioning

confidence: 99%

Investigation of flap flexibility of β-secretase using molecular dynamic simulations

Kumalo

Bhakat

Soliman

2015

Journal of Biomolecular Structure and Dynamics

View full text Add to dashboard Cite

Flap motif and its dynamics were extensively reported in aspartate proteases, e.g. HIV proteases and plasmepsins. Herein, we report the first account of flap dynamics amongst different conformations of β-secretase using molecular dynamics simulation. Various parameters were proposed and a selected few were picked which could appropriately describe the flap motion. Three systems were studied, namely Free (BACEFree) and two ligand-bound conformations, which belonged to space groups P6122 (BACEBound1) and C2221 (BACEBound2), respectively and four parameters (distance between the flaps tip residue, Thr72 and Ser325, d1; dihedral angle, ϕ (Thr72-Asp32-Asp228-Ser325); TriCα angles, θ1 (Thr72-Asp32-Ser325), and θ2 (Thr72-Asp228-Ser325)) were proposed to understand the change in dynamics of flap domain and the extent of flap opening and closing. Analysis of, θ2, d1, θ1 and ϕ confirmed that the BACEFree adopted semi-open, open and closed conformations with slight twisting during flap opening. However, BACEBound1 (P6122) showed an adaptation to open conformation due to lack of hydrogen bond interaction between the ligand and flap tip residue. A slight flap twisting, ϕ (lateral twisting) was observed for BACEBound1 during flap opening which correlates with the opening of BACEFree. Contradictory to the BACEBound1, the BACEBound2 locked the flap in a closed conformation throughout the simulation due to formation of a stable hydrogen bond interaction between the flap tip residue and ligand. Analyses of all three systems highlight that d1, θ2 and ϕ can be precisely used to describe the extent of flap opening and closing concurrently with snapshots along the molecular dynamics trajectory across several conformations of β-secretase.

show abstract

“…22 However, multiple groups have demonstrated that dynamics simulations provide complete sampling of the multiple flap conformations of HIV-1p. 23,24 Crystal structures are thought to provide a more accurate depiction of a protein despite the fact that NMR structures are solved in a more biologically relevant environment. [25][26][27] This may be due to the fact that X-ray crystallography generally provides a greater amount of high-quality experimental data than NMR spectroscopy, which can be assessed using standard quality control measurements.…”

Section: Introductionmentioning

confidence: 99%

Exploring Experimental Sources of Multiple Protein Conformations in Structure-Based Drug Design

2007

View full text Add to dashboard Cite

Receptor flexibility must be incorporated into structure-based drug design in order to portray a more accurate representation of a protein in solution. Our approach is to generate pharmacophore models based on multiple conformations of a protein and is very similar to solvent mapping of hot spots. Previously, we had success using computer-generated conformations of apo human immunodeficiency virus-1 protease (HIV-1p). Here, we examine the use of an NMR ensemble versus a collection of crystal structures, and we compare back to our previous study based on computer-generated conformations. To our knowledge, this is the first direct comparison of an NMR ensemble and a collection of crystal structures to incorporate protein flexibility in structure-based drug design. To provide an accurate comparison between the experimental sources, we used bound structures for our multiple protein structure (MPS) pharmacophore models. The models from an NMR ensemble and a collection of crystal structures were both able to discriminate known HIV-1p inhibitors from decoy molecules and displayed superior performance over models created from single conformations of the protein. Although the active-site conformations were already predefined by bound ligands, the use of MPS allows us to overcome the cross-docking problem and generate a model that does not simply reproduce the chemical characteristics of a specific ligand class. We show that there is more structural variation between 28 structures in an NMR ensemble than 90 crystal structures bound to a variety of ligands. MPS models from both sources performed well, but the model determined using the NMR ensemble appeared to be the most general yet accurate representation of the active site. This work encourages the use of NMR models in structure-based design.

show abstract

Flap opening mechanism of HIV-1 protease

Cited by 69 publications

References 41 publications

Targeting structural flexibility in HIV-1 protease inhibitor binding

Targeting structural flexibility in HIV-1 protease inhibitor binding

Investigation of flap flexibility of β-secretase using molecular dynamic simulations

Exploring Experimental Sources of Multiple Protein Conformations in Structure-Based Drug Design

Contact Info

Product

Resources

About