Atomistic models for free energy evaluation of drug binding to membrane proteins.

The binding of various molecules to integral membrane proteins with optimal affinity and specificity is central to normal function of cell. While membrane proteins represent about one third of the whole cell proteome, they are a majority of common drug targets. The quest for the development of computational models capable of accurate evaluation of binding affinities, decomposition of the binding into its principal components and thus mapping molecular mechanisms of binding remains one of the main goals of modern computational biophysics and related drug development. The primary scope of this review will be on the recent extension of computational methods for the study of drug binding to membrane proteins. Several examples of such applications will be provided ranging from secondary transporters to voltage gated channels. In this mini-review, we will provide a short summary on the breadth of different methods for binding affinity evaluation. These methods include molecular docking with docking scoring functions, molecular dynamics (MD) simulations combined with post-processing analysis using Molecular Mechanics/Poisson Boltzmann (Generalized Born) Surface Area (MM/PB(GB)SA), as well as direct evaluation of free energies from Free Energy Perturbation (FEP) with constraining schemes, and Potential of Mean Force (PMF) computations. We will compare advantages and shortcomings of popular techniques and provide discussion on the integrative strategies for drug development aimed at targeting membrane proteins.

Insights into the molecular mechanism of hERG1 channel activation and blockade by drugs.

Blockade of the human ether-a-go-go related gene 1 (hERG1) channel has been associated with an increased duration of ventricular repolarization, causing prolongation of the time interval between Q and T waves (long QT syndrome, or LQTS). LQTS may result in serious cardiovascular disorders such as tachyarrhythmia and sudden cardiac death. Diverse types of organic compounds bind to the wide intracellular cavity in the pore domain of hERG channels, leading to a full or partial blockade of ion current through the pore. The drug-induced blockade of the hERG-related component of the potassium current is thought to be a major reason for drug-induced arrhythmias in humans. Identification of specific interactions governing the high-affinity blockade of cardiac potassium (K-) channels is crucial both for the prevention of unintended ion channel block and for the design of ion channel modulators. A plethora of ligand- and receptor-based models of K-channels have been created to address these challenges. In this paper, we review the current state of knowledge regarding the structure-function relationship of hERG and discuss progress in the use of molecular modeling for developing both blockers and activators of hERG.

Free energy decomposition of protein-protein interactions.

A free energy decomposition scheme has been developed and tested on antibody-antigen and protease-inhibitor binding for which accurate experimental structures were available for both free and bound proteins. Using the x-ray coordinates of the free and bound proteins, the absolute binding free energy was computed assuming additivity of three well-defined, physical processes: desolvation of the x-ray structures, isomerization of the x-ray conformation to a nearby local minimum in the gas-phase, and subsequent noncovalent complex formation in the gas phase. This free energy scheme, together with the Generalized Born model for computing the electrostatic solvation free energy, yielded binding free energies in remarkable agreement with experimental data. Two assumptions commonly used in theoretical treatments; viz., the rigid-binding approximation (which assumes no conformational change upon complexation) and the neglect of vdW interactions, were found to yield large errors in the binding free energy. Protein-protein vdW and electrostatic interactions between complementary surfaces over a relatively large area (1400--1700 A(2)) were found to drive antibody-antigen and protease-inhibitor binding.