Accurately predicting protein–ligand binding affinities and binding modes is a major goal in computational chemistry, but even the prediction of ligand binding modes in proteins poses major ...challenges. Here, we focus on solving the binding mode prediction problem for rigid fragments. That is, we focus on computing the dominant placement, conformation, and orientations of a relatively rigid, fragment-like ligand in a receptor, and the populations of the multiple binding modes which may be relevant. This problem is important in its own right, but is even more timely given the recent success of alchemical free energy calculations. Alchemical calculations are increasingly used to predict binding free energies of ligands to receptors. However, the accuracy of these calculations is dependent on proper sampling of the relevant ligand binding modes. Unfortunately, ligand binding modes may often be uncertain, hard to predict, and/or slow to interconvert on simulation time scales, so proper sampling with current techniques can require prohibitively long simulations. We need new methods which dramatically improve sampling of ligand binding modes. Here, we develop and apply a nonequilibrium candidate Monte Carlo (NCMC) method to improve sampling of ligand binding modes. In this technique, the ligand is rotated and subsequently allowed to relax in its new position through alchemical perturbation before accepting or rejecting the rotation and relaxation as a nonequilibrium Monte Carlo move. When applied to a T4 lysozyme model binding system, this NCMC method shows over 2 orders of magnitude improvement in binding mode sampling efficiency compared to a brute force molecular dynamics simulation. This is a first step toward applying this methodology to pharmaceutically relevant binding of fragments and, eventually, drug-like molecules. We are making this approach available via our new Binding modes of ligands using enhanced sampling (BLUES) package which is freely available on GitHub.
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Sampling multiple binding modes of a ligand in a single molecular dynamics simulation is difficult. A given ligand may have many internal degrees of freedom, along with many different ways it might ...orient itself in a binding site or across several binding sites, all of which might be separated by large energy barriers. We have developed a novel Monte Carlo move called molecular darting (MolDarting) to reversibly sample between predefined binding modes of a ligand. Here, we couple this with nonequilibrium candidate Monte Carlo (NCMC) to improve acceptance of moves. We apply this technique to a simple dipeptide system, a ligand binding to T4 lysozyme L99A, and ligand binding to HIV integrase to test this new method. We observe significant increases in acceptance compared to uniformly sampling the internal and rotational/translational degrees of freedom in these systems.
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Flexible ligands often have multiple binding modes or bound conformations that differ by rotation of a portion of the molecule around internal rotatable bonds. Knowledge of these binding modes is ...important for understanding the interactions stabilizing the ligand in the binding pocket, and other studies indicate it is important for calculating accurate binding affinities. In this work, we use a hybrid molecular dynamics (MD)/nonequilibrium candidate Monte Carlo (NCMC) method to sample the different binding modes of several flexible ligands and also to estimate the population distribution of the modes. The NCMC move proposal is divided into three parts. The flexible part of the ligand is alchemically turned off by decreasing the electrostatics and steric interactions gradually, followed by rotating the rotatable bond by a random angle and then slowly turning the ligand back on to its fully interacting state. The alchemical steps prior to and after the move proposal help the surrounding protein and water atoms in the binding pocket relax around the proposed ligand conformation and increase move acceptance rates. The protein–ligand system is propagated using classical MD in between the NCMC proposals. Using this MD/NCMC method, we were able to correctly reproduce the different binding modes of inhibitors binding to two kinase targetsc-Jun N-terminal kinase-1 and cyclin-dependent kinase 2at a much lower computational cost compared to conventional MD and umbrella sampling. This method is available as a part of the BLUES software package.
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Binding Modes and Metabolism of Caffeine Jandova, Zuzana; Gill, Samuel C; Lim, Nathan M ...
Chemical research in toxicology,
07/2019, Volume:
32, Issue:
7
Journal Article
Peer reviewed
Open access
A correct estimate of ligand binding modes and a ratio of their occupancies is crucial for calculations of binding free energies. The newly developed method BLUES combines molecular dynamics with ...nonequilibrium candidate Monte Carlo. Nonequilibrium candidate Monte Carlo generates a plethora of possible binding modes and molecular dynamics enables the system to relax. We used BLUES to investigate binding modes of caffeine in the active site of its metabolizing enzyme Cytochrome P450 1A2 with the aim of elucidating metabolite-formation profiles at different concentrations. Because the activation energies of all sites of metabolism do not show a clear preference for one metabolite over the others, the orientations in the active site must play a key role. In simulations with caffeine located in a spacious pocket above the I-helix, it points N3 and N1 to the heme iron, whereas in simulations where caffeine is in close proximity to the heme N7 and C8 are preferably oriented toward the heme iron. We propose a mechanism where at low caffeine concentrations caffeine binds to the upper part of the active site, leading to formation of the main metabolite paraxanthine. On the other hand, at high concentrations two molecules are located in the active site, forcing one molecule into close proximity to the heme and yielding metabolites theophylline and trimethyluretic acid. Our results offer an explanation of previously published experimental results.
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Molecular simulations are a valuable tool for studying biomolecular motions and thermodynamics. However, such motions can be slow compared to simulation time scales, yet critical. Specifically, ...adequate sampling of side chain motions in protein binding pockets is crucial for obtaining accurate estimates of ligand binding free energies from molecular simulations. The time scale of side chain rotamer flips can range from a few ps to several hundred ns or longer, particularly in crowded environments like the interior of proteins. Here, we apply a mixed nonequilibrium candidate Monte Carlo (NCMC)/molecular dynamics (MD) method to enhance sampling of side chain rotamers. The NCMC portion of our method applies a switching protocol wherein the steric and electrostatic interactions between target side chain atoms and the surrounding environment are cycled off and then back on during the course of a move proposal. Between NCMC move proposals, simulation of the system continues via traditional molecular dynamics. Here, we first validate this approach on a simple, solvated valine-alanine dipeptide system and then apply it to a well-studied model ligand binding site in T4 lysozyme L99A. We compute the rate of rotamer transitions for a valine side chain using our approach and compare it to that of traditional molecular dynamics simulations. Here, we show that our NCMC/MD method substantially enhances side chain sampling, especially in systems where the torsional barrier to rotation is high (≥10 kcal/mol). These barriers can be intrinsic torsional barriers or steric barriers imposed by the environment. Overall, this may provide a promising strategy to selectively improve side chain sampling in molecular simulations.
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ABSTRACT
We observed a transit of WASP-166 b using nine Next Generation Transit Survey (NGTS) telescopes simultaneously with the Transiting Exoplanet Survey Satellite (TESS) observations of the same ...transit. We achieved a photometric precision of 152 ppm per 30 min with the nine NGTS telescopes combined, matching the precision reached by TESS for the transit event around this bright (T = 8.87) star. The individual NGTS light-curve noise is found to be dominated by scintillation noise and appears free from any time-correlated noise or any correlation between telescope systems. We fit the NGTS data for TC and Rp/R*. We find TC to be consistent to within 0.25σ of the result from the TESS data, and the difference between the TESS and NGTS measured Rp/R* values is 0.9σ. This experiment shows that multitelescope NGTS photometry can match the precision of TESS for bright stars, and will be a valuable tool in refining the radii and ephemerides for bright TESS candidates and planets. The transit timing achieved will also enable NGTS to measure significant transit timing variations in multiplanet systems.
ABSTRACT
We present the discovery of NGTS J0930−18, an extreme mass ratio eclipsing M-dwarf binary system with an early M-dwarf primary and a late M-dwarf secondary close to the hydrogen burning ...limit. Global modelling of photometry and radial velocities reveals that the secondary component (NGTS J0930−18 B) has a mass of M* = $0.0818 ^{+0.0040}_{-0.0015}$ M⊙ and radius of R* = $0.1059 ^{+0.0023}_{-0.0021}$ R⊙, making it one of the lowest mass stars with direct mass and radius measurements. With a mass ratio of q = $0.1407 ^{+0.0065}_{-0.017}$, NGTS J0930−18 has the lowest mass ratio of any known eclipsing M-dwarf binary system, posing interesting questions for binary star formation and evolution models. The mass and radius of NGTS J0930−18 B is broadly consistent with stellar evolutionary models. NGTS J0930−18 B lies in the sparsely populated mass radius parameter space close to the substellar boundary. Precise measurements of masses and radii from single lined eclipsing binary systems of this type are vital for constraining the uncertainty in the mass–radius relationship – of importance due to the growing number of terrestrial planets being discovered around low-mass stars.
ABSTRACT
The Transiting Exoplanet Survey Satellite has produced a large number of single-transit event candidates which are being monitored by the Next Generation Transit Survey (NGTS). We observed a ...second epoch for the TIC-231005575 system (Tmag = 12.06 and $T_{\rm eff} = 5500 \pm 85\, \mathrm{ K}$) with NGTS and a third epoch with Las Cumbres Observatory’s telescope in South Africa to constrain the orbital period ($P = 61.777\, \mathrm{ d}$). Subsequent radial velocity measurements with CORALIE revealed the transiting object has a mass of M2 = 0.128 ± 0.003 M⊙, indicating the system is a G-M binary. The radius of the secondary is R2 = 0.154 ± 0.008 R⊙ and is consistent with mesa models of stellar evolution to better than 1σ.
ABSTRACT
We present a study of the detection efficiency for the TESS mission, focusing on the yield of longer period transiting exoplanets (P > 25 d). We created the Transit Investigation and ...Recoverability Application (TIaRA) pipeline to use real TESS data with injected transits to create sensitivity maps which we combine with occurrence rates derived from Kepler. This allows us to predict longer period exoplanet yields, which will help design follow-up photometric and spectroscopic programs, such as the NGTS (Next Generation Transit Survey) Monotransit Program. For the TESS Years 1 and 3 SPOC (Science Processing Operations Centre) FFI (Full Frame Image) light curves, we find $2271^{+241}_{-138}$ exoplanets should be detectable around AFGKM dwarf host stars. We find $215^{+37}_{-23}$ exoplanets should be detected from single-transit events or ‘monotransits’. An additional $113^{+22}_{-13}$ detections should result from ‘biennial duotransit’ events with one transit in Year 1 and a second in Year 3. We also find that K dwarf stars yield the most detections by TESS per star observed. When comparing our results to the TOI (TESS objects of interest) catalogue, we find our predictions agree within 1σ of the number of discovered systems with periods between 0.78 and 6.25 d and agree to 2σ for periods between 6.25 and 25 d. Beyond periods of 25 d, we predict $403^{+64}_{-38}$ detections, which is three times as many detections as there are in the TOI catalogue with >3σ confidence. This indicates a significant number of long-period planets yet to be discovered from TESS data as monotransits or biennial duotransits.
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