Room 505, Cosmology Building, National Taiwan University + Cisco WebEx, Physical+Online Seminar
(實體+線上演講 台灣大學次震宇宙館505研討室+ Cisco WebEx)
A Method to Build a Markov State Model of K Channel Permeation from Molecular Dynamics Data
Luigi Catacuzzeno (University of Perugia)
Abstract
Molecular dynamic (MD) simulation of protein conformational changes has always been a very challenging task due to the long timescales of the processes involved, compared to those that can be simulated, and the challenges associated with handling the large amount of data resulting from MD simulations. Recently, we have witnessed the introduction of Markov state models (MSMs) in this area of research, which have soon proven to be very effective in addressing both challenges, as they provide a mechanistically comprehensible synthesis (a simplified kinetic model) of the large amount of MD data and at the same time can simulate the long timescales of biological processes (protein dynamics), thus confronting experimental data.
Of the many studies on protein simulation and the MSM-assisted approach, only very few have addressed ion channel permeation, and above all, none of these have ever tried to deal with the charges (carried by ions) passing through the channels, which are ultimately crucial for predicting the ion current to be compared with experimental results.
In this talk, I present a method for building a MSM of ion channel permeation that correctly evaluates the current flowing through the channel, associated with the ion flux. In essence, this is done by including in the model the definition of a flux matrix appropriately built to be used in conjunction with the transition matrix to predict the ion current. In applying this strategy, we faced some serious problems, such as, for example, the availability of a flux matrix only at lagtimes that do not guarantee the markovianity of the model. I will show you how we solved this and other related problems, finally obtaining an MSM simple enough to be easily understood, but above all capable, for the first time, of predicting with great accuracy the current flowing through the channel. Finally, we applied the method to MD data obtained on KcsA channels at varying voltages, and we were able to obtain a four state MSM with Woodhull-shaped voltage-dependent kinetic rate constants, able to reproduce with accuracy the channel I-V relationship.
Meeting number (access code): 2517 000 9942
Meeting password: 59mgAmsdej4
Organizer: Tzyy-Leng Horng (FCU)
