Accelerated structure-based design of chemically diverse allosteric modulators of a muscarinic G protein-coupled receptor.

Design of ligands that provide receptor selectivity has emerged as a new paradigm for drug discovery of G protein-coupled receptors, and may, for certain families of receptors, only be achieved via identification of chemically diverse allosteric modulators. Here, the extracellular vestibule of the M2 muscarinic acetylcholine receptor (mAChR) is targeted for structure-based design of allosteric modulators. Accelerated molecular dynamics (aMD) simulations were performed to construct structural ensembles that account for the receptor flexibility.

Docking and free energy perturbation studies of ligand binding in the kappa opioid receptor.

The kappa opioid receptor (KOR) is an important target for pain and depression therapeutics that lack harmful and addictive qualities of existing medications. We present a model for the binding of morphinan ligands and JDTic to the JDTic/KOR crystal structure based on an atomic level description of the water structure within its active site. The model contains two key interaction motifs that are supported by experimental evidence.

Prediction of Long Loops with Embedded Secondary Structure using the Protein Local Optimization Program.

Robust homology modeling to atomic-level accuracy requires in the general case successful prediction of protein loops containing small segments of secondary structure. Further, as loop prediction advances to success with larger loops, the exclusion of loops containing secondary structure becomes awkward. Here, we extend the applicability of the Protein Local Optimization Program (PLOP) to loops up to 17 residues in length that contain either helical or hairpin segments.

Computational methods for high resolution prediction and refinement of protein structures.

We review advances in implicit solvation and sampling algorithms which have resulted in enhanced capabilities in predicting and refining localized protein structures (e.g. loop regions) to high resolution.

The protein local optimization program and G-protein-coupled receptors: loop restoration and applications to homology modeling.

The protein local optimization program (PLOP) uses sophisticated sampling algorithms and a highly refined physics-based energy function to restore loops within a protein structure. In this chapter, we highlight some of the recent successes we have had with PLOP restoring long loops in their native environment as well as the intra- and extracellular loops of four G-protein-coupled receptors. This includes the very long second extracellular loops of bovine rhodopsin and the turkey β1- and human β2-adrenergic receptors.

Loop prediction for a GPCR homology model: algorithms and results.

We present loop structure prediction results of the intracellular and extracellular loops of four G-protein-coupled receptors (GPCRs): bovine rhodopsin (bRh), the turkey β1-adrenergic (β1Ar), the human β2-adrenergic (β2Ar) and the human A2a adenosine receptor (A2Ar) in perturbed environments. We used the protein local optimization program, which builds thousands of loop candidates by sampling rotamer states of the loops' constituent amino acids. The candidate loops are discriminated between with our physics-based, all-atom energy function, which is based on the OPLS force field with implicit solvent and several correction terms.

Successful prediction of the intra- and extracellular loops of four G-protein-coupled receptors.

We present results of the restoration of all crystallographically available intra- and extracellular loops of four G-protein-coupled receptors (GPCRs): bovine rhodopsin (bRh), the turkey β-1 adrenergic receptor (β1Ar), and the human β-2 adrenergic (β2Ar) and A2A adenosine (A2Ar) receptors. We use our Protein Local Optimization Program (PLOP), which samples conformational space from first principles to build sets of loop candidates and then discriminates between them using our physics-based, all-atom energy function with implicit solvent. We also discuss a new kind of explicit membrane calculation developed for GPCR loops that interact, either in the native structure or in low-energy false-positive structures, with the membrane, and thus exist in a multiphase environment not previously incorporated in PLOP.

Localized orbital corrections for the calculation of barrier heights in density functional theory.

This work describes the extension of a previously reported empirical localized orbital correction model for density functional theory (DFT-LOC) for atomization energies, ionization potentials, electron affinities, and reaction enthalpies to the correction of barrier heights for chemical reactions of various types including cycloadditions, cycloreversions, dipolar cycloadditions, S(N)2's, carbon radical reactions, hydrogen radical reactions, sigmatropic shifts, and electrocyclizations. The B3LYP localized orbital correction version of the model (B3LYP-LOC) reduces the number of outliers and overall mean unsigned error (MUE) vs. experiment or ab initio values from 3.

Localized orbital corrections applied to thermochemical errors in density functional theory: The role of basis set and application to molecular reactions.

This paper is a logical continuation of the 22 parameter, localized orbital correction (LOC) methodology that we developed in previous papers [R. A. Friesner et al.

Origins of stereoselectivity in the oxido-alkylidenation of alkynes.

A mild, convenient oxido-alkylidenation of alkynes is described. The three-step sequence involves the 1,3-dipolar cycloaddition of a nitrone and an alkynoate, oxidation of the resulting isoxazoline, and stereoselective extrusion of nitrosomethane. Quantum mechanical calculations identified the interactions of R3 with the oxidant and the preferred conformation of a diradical intermediate as major factors controlling the stereoselectivity of the oxidation and torquoselectivity of the extrusion.