modelling ion channels -H

Question 1

Different types of ion channel models and what they aim to model

Answer 1

Structural, molecular dynamics, and kinetic models (e.g., mechanistic and Markov)

They aim to identify how the ion channel opens/closes, what states it can occupy, binding and gating mechanisms, and to define the kinetics for ion channel functions (e.g., activation, desensitisation, etc…)

This will be used to translate structure into function.

Question 2

Del Castillo-Katz model overview

Answer 2

Makes binding and gating separate steps.

The ion channel can be closed and vacant, closed and occupied, or open and occupied.

A + R -> AR -> AR*

KA measures the binding of the ligand to the receptor.

E measures the likelihood of the ion channel then opening. Intrinsic efficacy.

Question 3

Limitations of the Castillo-Katz model in utilising population data

Answer 3

Binding affinity when measuered experimentally is actually measuring the occupancy of the population of receptors in multiple states.

This is not equivalent to measuring the equilibrium constant for the agonist binding step, as changes in agonist efficacy will directly change binding affinity even without there being any changes to the binding step.

All states of the receptor will contribute to the experimental measures of binding and activation.

Intrinsic affinity and efficacy cannot be extracted from experimental data on populations.

Question 4

Markov model overview

Answer 4

Utilising the law of mass action, it assumes that state transitions have no memory.

Rate constants are probabilities, where open/shut times and burst lengths have exponential distributions.

All ion channels have so many states that it becomes algebraically intractable to calculate. Can be done computationally though.

Question 5

What are the values of kinetic modelling

Answer 5

it links experimental results to a reasonable approximation of reality.

Aids in understanding MOA

Allows testing of specific claims, such as the effect on Kd of binding site mutations

Can allow for impossible experiments (such as decreasing efficacy 10-fold, etc…)

And can be used to predict pharmacology.