Article

Predicting Ligand Binding Affinity with Alchemical Free Energy Methods in a Polar Model Binding Site

Graduate Group in Biophysics, University of California-San Francisco, San Francisco, CA 94158-2518, USA
Journal of Molecular Biology (Impact Factor: 3.96). 12/2009; 394(4):747-763. DOI: 10.1016/j.jmb.2009.09.049

ABSTRACT We present a combined experimental and modeling study of organic ligand molecules binding to a slightly polar engineered cavity site in T4 lysozyme (L99A/M102Q). For modeling, we computed alchemical absolute binding free energies. These were blind tests performed prospectively on 13 diverse, previously untested candidate ligand molecules. We predicted that eight compounds would bind to the cavity and five would not; 11 of 13 predictions were correct at this level. The RMS error to the measurable absolute binding energies was 1.8 kcal/mol. In addition, we computed “relative” binding free energies for six phenol derivatives starting from two known ligands: phenol and catechol. The average RMS error in the relative free energy prediction was 2.5 kcal/mol (phenol) and 1.1 kcal/mol (catechol). To understand these results at atomic resolution, we obtained x-ray co-complex structures for nine of the diverse ligands and for all six phenol analogs. The average RMSD of the predicted pose to the experiment was 2.0 Å (diverse set), 1.8 Å (phenol-derived predictions), and 1.2 Å (catechol-derived predictions). We found that predicting accurate affinities and rank-orderings required near-native starting orientations of the ligand in the binding site. Unanticipated binding modes, multiple ligand binding, and protein conformational change all proved challenging for the free energy methods. We believe that these results can help guide future improvements in physics-based absolute binding free energy methods.

Download full-text

Full-text

Available from: Ken A Dill, Jun 30, 2015
0 Followers
 · 
102 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The authors propose a wide area distributed shared memory (DSM) system in which the memory hierarchy is integrated into the switching network. The system requires only one message to access a mobile shared object, as compared to two in a directory-based approach. The authors simulated a wide-area DSM on the NSFNET and showed that the approach reduced memory fault delay significantly
    Distributed Computing Systems, 1993., Proceedings of the Fourth Workshop on Future Trends of; 10/1993
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The authors propose a method for deriving parallel, scheduling-optimized protocol implementations from sequential protocol specifications. They start with an SDL specification, identify a common path for optimization, and perform a data dependency analysis. The resulting common path graph is parallelized as far as permitted by the data dependency graph. The degree of parallelism is extended even further by deferring data operations to the exit nodes of the common path graph. The resulting parallel operation model is then submitted to a scheduling algorithm, yielding an optimized compile-time schedule. An IP-based protocol stack with TCP and FTP as upper layers serves as an example
    Distributed Computing Systems, 1993., Proceedings of the Fourth Workshop on Future Trends of; 10/1993
  • [Show abstract] [Hide abstract]
    ABSTRACT: An earlier study of the activation and deactivation characteristics of p- and n-type dopant materials in shallow pre-amorphized silicon layers showed varying melt depth for a constant laser energy with varying dopant species. Possible causes of this variation could be attributed to either laser repeatability issues on early test equipment or a species-related laser absorption effects. Species dependence process windows are of serious concern for minimizing process complexity in CMOS wafer manufacturing. This paper reports the results of an investigation into the dependence of laser annealed junction depth in germanium pre-amorphized silicon layers on varying doses of boron, arsenic: and phosphorus dopant species. A 10 keV, 1×10<sup>15</sup> ions/cm<sup>2</sup> germanium implant was used to amorphize the silicon surface and set the laser annealed junction depth. Low energy implantation was used to introduce 1 keV boron, 2 keV phosphorus and 5 keV arsenic at doses of 1×10<sup>15</sup> and 3×10<sup>15</sup> ions/cm<sup>2</sup> into the amorphous region. Laser thermal annealing was performed at energies from 0.3 to 0.68 J/cm <sup>2</sup>. Four-point probe and secondary ion mass spectrometry analysis data are presented
    Ion Implantation Technology, 2000. Conference on; 02/2000