HIV-1 protease flaps spontaneously open and reclose in molecular dynamics simulations

Horn̆ák, Viktor; Okur, Asim; Rizzo, Robert C.; Simmerling, Carlos

doi:10.1073/pnas.0508452103

Cited by 353 publications

(490 citation statements)

References 35 publications

Supporting

Mentioning

451

Contrasting

Unclassified

Order By: Relevance

“…That these conformational changes correspond to channel opening is supported by SCAM experiments upon agonist binding (10,19). Our study provides atomic-scale mechanistic insight to nAChR in particular and contributes to the understanding of spontaneous conformational changes in protein function and regulation (29)(30)(31) in general.…”

Section: Resultssupporting

confidence: 56%

Spontaneous conformational change and toxin binding in α7 acetylcholine receptor: Insight into channel activation and inhibition

Tjong

Zhou

2008

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Nicotinic AChRs (nAChRs) represent a paradigm for ligand-gated ion channels. Despite intensive studies over many years, our understanding of the mechanisms of activation and inhibition for nAChRs is still incomplete. Here, we present molecular dynamics (MD) simulations of the ␣7 nAChR ligand-binding domain, both in apo form and in ␣-Cobratoxin-bound form, starting from the respective homology models built on crystal structures of the acetylcholine-binding protein. The toxin-bound form was relatively stable, and its structure was validated by calculating mutational effects on the toxin-binding affinity. However, in the apo form, one subunit spontaneously moved away from the conformation of the other four subunits. This motion resembles what has been proposed for leading to channel opening. At the top, the C loop and the adjacent ␤7-␤8 loop swing downward and inward, whereas at the bottom, the F loop and the C terminus of ␤10 swing in the opposite direction. These swings appear to tilt the whole subunit clockwise. The resulting changes in solvent accessibility show strong correlation with experimental results by the substituted cysteine accessibility method upon addition of acetylcholine. Our MD simulation results suggest a mechanistic model in which the apo form, although predominantly sampling the ''closed'' state, can make excursions into the ''open'' state. The open state has high affinity for agonists, leading to channel activation, whereas the closed state upon distortion has high affinity for antagonists, leading to inhibition.allostery ͉ spontaneous opening ͉ ligand-gated ion channel ͉ ligand binding N icotinic AChRs (nAChRs) are a well studied prototype for ligand-gated ion channels (1-19). nAChRs are pentamers consisting of either homo or hetero subunits. The N-terminal extracellular regions of the subunits make up the ligand-binding domain (LBD), with two or five binding sites in hetero and homo pentamers, respectively. The central regions form the transmembrane domain (TMD), which is an ion channel selective for cations such as Na ϩ , K ϩ , and Ca 2ϩ [supporting information (SI) Fig. S1]. A central issue is the mechanisms of channel activation by agonists and inhibition by antagonists. How is agonist/ antagonist binding transmitted to trigger channel opening/ closing? What are the necessary conformational changes? Experimental and computational studies together have begun to provide mechanistic insights at the atomic level. Here, we present a molecular dynamics (MD) simulation study of the ␣7 nAChR LBD (consisting of five ␣-type subunits), both in apo form and in ␣-Cobratoxin-bound form. Our simulation results are in broad agreement with a wealth of experimental data. Combining the present work with experimental data and previous computational results, we propose a mechanistic model in which the apo form, although predominantly sampling the ''closed'' state, can make excursions into the ''open'' state. Details of the conformational change leading to channel activation/inhibition are presented.A number ...

show abstract

Section: Resultssupporting

confidence: 56%

Spontaneous conformational change and toxin binding in α7 acetylcholine receptor: Insight into channel activation and inhibition

Tjong

Zhou

2008

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…For this reason, we extensively used these parameters on a variety of systems not discussed here before making this report. For example, the improved glycine parametrization was important in our recent simulations of HIV-1 protease 70 , where glycine rich "flaps" play an essential role in protease dynamics. Another study 69 reported a hybrid replica exchange method, where ff99SB was used to test the methodology based on conformational sampling of polyalanine peptides of varying lengths.…”

Section: Discussionmentioning

confidence: 99%

Comparison of multiple Amber force fields and development of improved protein backbone parameters

et al. 2006

Self Cite

View full text Add to dashboard Cite

The ff94 force field that is commonly associated with the AMBER simulation package is one of the most widely used parameter sets for biomolecular simulation. After a decade of extensive use and testing, limitations in this force field, such as over stabilization of α-helices, were reported by us and other researchers. This led to a number of attempts to improve these parameters, resulting in a variety of "AMBER" force fields and significant difficulty in determining which should be used for a particular application. We show that several of these continue to suffer from inadequate balance between different secondary structure elements. In addition, the approach used in most of these studies neglected to account for the existence in AMBER of two sets of backbone φ/ψ dihedral terms. This led to parameter sets that provide unreasonable conformational preferences for glycine. We report here an effort to improve the φ/ψ dihedral terms in the ff99 energy function. Dihedral term parameters are based on fitting the energies of multiple conformations of glycine and alanine tetrapeptides from high level ab-initio quantum mechanical calculations. The new parameters for backbone dihedrals replace those in the existing ff99 force field. This parameter set, which we denote ff99SB, achieves a better balance of secondary structure elements as judged by improved distribution of backbone dihedrals for glycine and alanine with respect to PDB survey data. It also accomplishes improved agreement with published experimental data for conformational preferences of short alanine peptides, and better accord with experimental NMR relaxation data of test protein systems.

show abstract

“…A related approach directly compares spectral density components J(ω), 16 whereby the extraction of spectral densities from the experiment requires additional experiments or makes additional assumptions. 29 Here, we report the results of molecular dynamics trajectories of the well-characterized protein ubiquitin computed in the AMBER software package, 30 using both the AMBER99 31 and the modified AMBER99SB 24,25 force fields. Several sets of experimental NMR spin relaxation data have been published for ubiquitin, [32][33][34][35][36] making it a valuable model system for assaying the quantitative accuracy of the MDderived NMR relaxation parameters.…”

Section: Introductionmentioning

confidence: 99%

Validation of Molecular Dynamics Simulations of Biomolecules Using NMR Spin Relaxation as Benchmarks: Application to the AMBER99SB Force Field

Showalter

Brüschweiler

2007

J. Chem. Theory Comput.

252

277

View full text Add to dashboard Cite

Biological function of biomolecules is accompanied by a wide range of motional behavior. Accurate modeling of dynamics by molecular dynamics (MD) computer simulations is therefore a useful approach toward the understanding of biomolecular function. NMR spin relaxation measurements provide rigorous benchmarks for assessing important aspects of MD simulations, such as the amount and time scales of conformational space sampling, which are intimately related to the underlying molecular mechanics force field. Until recently, most simulations produced trajectories that exhibited too much dynamics particularly in flexible loop regions. Recent modifications made to the backbone and ψ torsion angle potentials of the AMBER and CHARMM force fields indicate that these changes produce more realistic molecular dynamics behavior. To assess the consequences of these changes, we performed a series of 5-20 ns molecular dynamics trajectories of human ubiquitin using the AMBER99 and AMBER99SB force fields for different conditions and water models and compare the results with NMR experimental backbone N-H S 2 order parameters. A quantitative analysis of the trajectories shows significantly improved agreement with experimental NMR data for the AMBER99SB force field as compared to AMBER99. Because NMR spin relaxation data (T 1 , T 2 , NOE) reflect the combined effects of spatial and temporal fluctuations of bond vectors, it is found that comparison of experimental and back-calculated NMR spin-relaxation data provides a more objective way of assessing the quality of the trajectory than order parameters alone. Analysis of a key mobile -hairpin in ubiquitin demonstrates that the dynamics of mobile sites are not only reduced by the modified force field, but the extent of motional correlations between amino acids is also markedly diminished.

show abstract

HIV-1 protease flaps spontaneously open and reclose in molecular dynamics simulations

Cited by 353 publications

References 35 publications

Spontaneous conformational change and toxin binding in α7 acetylcholine receptor: Insight into channel activation and inhibition

Spontaneous conformational change and toxin binding in α7 acetylcholine receptor: Insight into channel activation and inhibition

Comparison of multiple Amber force fields and development of improved protein backbone parameters

Validation of Molecular Dynamics Simulations of Biomolecules Using NMR Spin Relaxation as Benchmarks: Application to the AMBER99SB Force Field

Contact Info

Product

Resources

About