Computational Methods of Studying the Binding of Toxins From Venomous Animals to Biological Ion Channels: Theory and Applications

Abstract

The discovery of new drugs that selectively block or modulate ion channels has great potential to provide new treatments for a host of conditions. One promising avenue revolves around modifying or mimicking certain naturally occurring ion channel modulator toxins. This strategy appears to offer the prospect of designing drugs that are both potent and specific. The use of computational modeling is crucial to this endeavor, as it has the potential to provide lower cost alternatives for exploring the effects of new compounds on ion channels. In addition, computational modeling can provide structural information and theoretical understanding that is not easily derivable from experimental results. In this review, we look at the theory and computational methods that are applicable to the study of ion channel modulators. The first section provides an introduction to various theoretical concepts, including force-fields and the statistical mechanics of binding. We then look at various computational techniques available to the researcher, including molecular dynamics, brownian dynamics, and molecular docking systems. The latter section of the review explores applications of these techniques, concentrating on pore blocker and gating modifier toxins of potassium and sodium channels. After first discussing the structural features of these channels, and their modes of block, we provide an in-depth review of past computational work that has been carried out. Finally, we discuss prospects for future developments in the field.

Mechanism of μ-Conotoxin PIIIA Binding to the Voltage-Gated Na+ Channel NaV1.4

“…Based on the PMF profile the K d value for the formation of the toxin-channel complex can be calculated rigorously according to eq. 1 [27]. It is worth noting that K d and IC 50 have been used interchangeably as it may be assumed that the experimentally measured IC 50 and the true K d values are in the same order.…”

Mechanisms and Energetics of Potassium Channel Block by Local Anesthetics and Antifungal Agents

“…The potential of mean force (PMF) profiles for the binding of drug molecules and a permeating K + ion to the inner cavity of Kv1.2 and K Ca 3.1 are constructed using the umbrella sampling method. The K d values for drug binding are derived according to the following equation: 34,35 …”

Computational Approaches for Designing Potent and Selective Analogs of Peptide Toxins as Novel Therapeutics

“…This provided an important test case for the viability of the method because the structure of the complex was known [34], and there was no uncertainty in that regard. Since then, the PMF method has been used in several computational studies of toxin binding to ion channels (see [11,12] for reviews). Provided that a validated complex structure was employed and the PMF was calculated properly, the standard binding free energy was obtained accurately in all cases.…”

“…Most of the computational work on toxin binding to ion channels has been done on potassium channels [11,12], because their crystal structures have been available since 1998 [62]. Here we will focus on Kv1 channels, and in particular Kv1.3, which is an established target for the treatment of autoimmune diseases.…”

“…Binding modes obtained from such models provide valuable hints for identifying suitable mutations that could achieve the desired selectivity. Second, one can perform free-energy calculations to determine the binding free energies of toxins and their analogs from potential of mean force (PMF) calculations or predict the effect of mutations directly from free-energy perturbation (FEP) calculations [11–16]. Here we give a brief review of computational methods used in the construction of channel–toxin complexes and the calculation of absolute and relative binding free energies in such complexes.…”