BcompB meeting on simulations methods for allosteric signal propagation
Tuesday July 16th, 2-3pm, C42
Our next BcompB meeting will take place on July 16th, 2-3pm in C42. We will hear about and discuss simulation methods to look into allosteric communication/signal propagation.
Eric Lang and Sofia Oliveira will be speaking about methods that they have developed and applied.
Calculated pKa Variations Expose Dynamic Allosteric Communication Networks
Allosteric regulation of protein function, the process by which binding of an effector molecule provokes a functional response from a distal site, is critical for metabolic pathways. Yet, the way the allosteric signal is communicated remains elusive, especially in dynamic, entropically driven regulation mechanisms for which no major conformational changes are observed. To identify these dynamic allosteric communication networks, we have developed an approach that monitors the pKa variations of ionizable residues over the course of molecular dynamics simulations performed in the presence and absence of an allosteric regulator. As the pKa of ionizable residues depends on their environment, it represents a simple metric to monitor changes in several complex factors induced by binding an allosteric effector. These factors include Coulombic interactions, hydrogen bonding, and solvation, as well as backbone motions and side chain fluctuations. The predictions that can be made with this method concerning the roles of ionizable residues for allosteric communication can then be easily tested experimentally by changing the working pH of the protein or performing single point mutations.
Signal propagation in nicotinic receptors: contributions from equilibrium and nonequilibrium simulations
Nicotinic acetylcholine receptors (nAChRs) modulate synaptic transmission in the nervous system. These receptors have emerged as therapeutic targets in drug discovery for treating several conditions, including Alzheimer’s, pain and nicotine addiction. Despite the impressive progress made in the study of this family of receptors, the conformational changes induced by agonist binding/unbinding and how those are communicated to the ion channel remain poorly defined. This is fundamentally important for understanding biological function as well as crucial for rational drug discovery. Here, we have developed a novel computational strategy combing extensive equilibrium and nonequilibrium molecular dynamics simulations to map dynamic and structural changes induced by nicotine in the human α4β2 nAChR. This approach revealed a striking pattern of communication between the binding pockets and the transmembrane domains and allowed for the identification of the sequence of conformational changes associated with the initial steps in this process.