Method for Computing Protein Binding Affinity

A Monte Carlo method is given to compute the binding affinity of a ligand to a protein. The method involves extending configuration space by a discrete variable indicating whether the ligand is bound to the protein and a special Monte Carlo move which allows transitions between the unbound and bound states. Provided that an accurate protein structure is given, that the protein-ligand binding site is known, and that an accurate chemical force field together with a continuum solvation model is used, this method provides a quantitative estimate of the free energy of binding.Comment: RevTex, 10 pages with 5 figures. Explanatory figure adde

Inclusion of Enclosed Hydration Effects in the Binding Free Energy Estimation of Dopamine D3 Receptor Complexes

Confined hydration and conformational flexibility are some of the challenges encountered for the rational design of selective antagonists of G-protein coupled receptors. We present a set of C3-substituted (-)-stepholidine derivatives as potent binders of the dopamine D3 receptor. The compounds are characterized biochemically, as well as by computer modeling using a novel molecular dynamics-based alchemical binding free energy approach which incorporates the effect of the displacement of enclosed water molecules from the binding site. The free energy of displacement of specific hydration sites is obtained using the Hydration Site Analysis method with explicit solvation. This work underscores the critical role of confined hydration and conformational reorganization in the molecular recognition mechanism of dopamine receptors and illustrates the potential of binding free energy models to represent these key phenomena.Comment: This is the first report of using enclosed hydration in estimating binding free energies of protein-ligand complexes using implicit solvatio

Open Boundary Simulations of Proteins and Their Hydration Shells by Hamiltonian Adaptive Resolution Scheme

The recently proposed Hamiltonian Adaptive Resolution Scheme (H-AdResS) allows to perform molecular simulations in an open boundary framework. It allows to change on the fly the resolution of specific subset of molecules (usually the solvent), which are free to diffuse between the atomistic region and the coarse-grained reservoir. So far, the method has been successfully applied to pure liquids. Coupling the H-AdResS methodology to hybrid models of proteins, such as the Molecular Mechanics/Coarse-Grained (MM/CG) scheme, is a promising approach for rigorous calculations of ligand binding free energies in low-resolution protein models. Towards this goal, here we apply for the first time H-AdResS to two atomistic proteins in dual-resolution solvent, proving its ability to reproduce structural and dynamic properties of both the proteins and the solvent, as obtained from atomistic simulations.Comment: This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Chemical Theory and Computation, copyright \c{opyright} American Chemical Society after peer review and technical editing by the publishe

Extending fragment-based free energy calculations with library Monte Carlo simulation: Annealing in interaction space

Pre-calculated libraries of molecular fragment configurations have previously been used as a basis for both equilibrium sampling (via "library-based Monte Carlo") and for obtaining absolute free energies using a polymer-growth formalism. Here, we combine the two approaches to extend the size of systems for which free energies can be calculated. We study a series of all-atom poly-alanine systems in a simple dielectric "solvent" and find that precise free energies can be obtained rapidly. For instance, for 12 residues, less than an hour of single-processor is required. The combined approach is formally equivalent to the "annealed importance sampling" algorithm; instead of annealing by decreasing temperature, however, interactions among fragments are gradually added as the molecule is "grown." We discuss implications for future binding affinity calculations in which a ligand is grown into a binding site

Quasi-Chemical Theory and Implicit Solvent Models for Simulations

A statistical thermodynamic development is given of a new implicit solvent model that avoids the traditional system size limitations of computer simulation of macromolecular solutions with periodic boundary conditions. This implicit solvent model is based upon the quasi-chemical approach, distinct from the common integral equation trunk of the theory of liquid solutions. The physical content of this theory is the hypothesis that a small set of solvent molecules are decisive for these solvation problems. A detailed derivation of the quasi-chemical theory escorts the development of this proposal. The numerical application of the quasi-chemical treatment to Li$^+$ ion hydration in liquid water is used to motivate and exemplify the quasi-chemical theory. Those results underscore the fact that the quasi-chemical approach refines the path for utilization of ion-water cluster results for the statistical thermodynamics of solutions.Comment: 30 pages, contribution to Santa Fe Workshop on Treatment of Electrostatic Interactions in Computer Simulation of Condensed Medi

Cellular Ability to Sense Spatial Gradients in the Presence of Multiple Competitive Ligands

Many eukaryotic and prokaryotic cells can exhibit remarkable sensing ability under small gradient of chemical compound. In this study, we approach this phenomenon by considering the contribution of multiple ligands to the chemical kinetics within Michaelis-Menten model. This work was inspired by the recent theoretical findings from Bo Hu et al. [Phys. Rev. Lett. 105, 048104 (2010)], our treatment with practical binding energies and chemical potential provides the results which are consistent with experimental observations.Comment: 5 pages, 4 figure

The study of allosteric modulator sites at the cannabinoid CB1 receptor

Org 27569, Org 27759 and Org 29647 are the first discovered allosteric modulators of the cannabinoid CB1 receptor. These ligands are thought to bind to "accessory binding sites" at the receptor . Binding of the Org allosteric modulators has been shown to affect the affinities of various CB1 ligands, but to reduce the efficacy of these ligands. The goal of this research project was to understand at a molecular level, the origins of the effects produced by the Org allosteric modulators. The study was begun by performing AM1 conformational searches for each allosteric modulator using the Spartan molecular modeling suite . Those conformers within 2.00 kcal/mol of the global minimum energy conformer of each modulator were subjected to geometry optimization in Jaguar (Schrodinger, Inc). Org27569 was then targeted for further study. Org 27569 has been reported to increase the CB1 affinity of the non-classical cannabinoid, (1R3R4R)-3-[2-hydroxy-4-(1,1-dimethylheptylphenyl]-4-(3-hydroxy-propyl)cyclohexab-1-ol, CP-55,940, but to reduce its efficacy. Since the binding site of Org27569 is unknown, the MMC program was then employed to identify potential binding sites. The MMC program is a cavity biased method that uses Monte Carlo simulated annealing of chemical potential to identify small-molecule binding sites in protein structures via a molecular fragment approach [F. Guarnieri and M. Mezei,JACS 118, 8493, 1996]. The receptor was placed in a virtual cell. At high chemical potentials, the box is filled with completely with the fragment of interest. As the chemical potential decreases, fragments with less favorable interactions are stripped away. Indole and piperidine rings were used as fragments because they constitute the two major structural features of Org 27569. Three common binding sites for both the indole and piperidine fragments were identified. These areas were R3.50 (intracellular domain), W4.50 (possible homodimer interface) and in the transmembrane region between helices 1 and 2 (interacting with CP55,940). These were considered possible interaction sites for the following reasons: (1) If interactions occurred between the allosteric modulator and R3.50, this would block the interaction site of the G-protein and thus impair signalling. (2) W4.50 is commonly found in GPCR dimer interfaces. If the CB1 receptor functions as a dimer, Org27569 would impair activation by blocking dimer formation. (3) The TMH1-2 site site would allow the affinity of CP55940 to increase because it would block CP55940 exit from CB1. At the same time, the TMH1-2 site dock would constrain TMH6 from moving during activation by tethering the EC-3 loop. This should also result in impaired signal transduction. Future studies will involve mutation studies of each allosteric binding site identified in this project to determine the allosteric binding site for Org 27569

Steric interactions between mobile ligands facilitate complete wrapping in passive endocytosis

Receptor-mediated endocytosis is an ubiquitous process through which cells internalize biological or synthetic nanoscale objects, including viruses, unicellular parasites, and nanomedical vectors for drug or gene delivery. In passive endocytosis the cell plasma membrane wraps around the "invader" particle driven by ligand-receptor complexation. By means of theory and numerical simulations, here we demonstrate how particles decorated by freely diffusing and non-mutually-interacting (ideal) ligands are significantly more difficult to wrap than those where ligands are either immobile or interact sterically with each other. Our model rationalizes the relationship between uptake mechanism and structural details of the invader, such as ligand size, mobility and ligand/receptor affinity, providing a comprehensive picture of pathogen endocytosis and helping the rational design of efficient drug delivery vectors.Comment: Updated version of the manuscript. Accepted for publication in PR