TCBG Seminar

Increasing the realism of MD simulations by adding pH effects

Miguel Machuqueiro
BioISI - Instituto de Biosistemas e Ciencias Integrativas
Faculdade de Ciencias, Universidade de Lisboa
Lisboa, Portugal

Monday, February 19, 2024
3:00 pm (CT)
Zoom webinar recording


pH is a crucial physicochemical property that affects most biomolecules. Changes in the protonation equilibrium of susceptible protein sites will modify the electrostatic environment and, consequently, affect their structure, stability, and catalysis. The pKa values of titrable sites in peptides, proteins, and drugs can be significantly influenced by changes in their local environment, including when they interact with (insert into) a lipid bilayer. In some cases, like the tumor microenvironment (TME), the solution pH can also change, leading to changes in protein stability, ligand binding, and even drug membrane permeabilities. In this work, I will present data obtained with our constant-pH MD methodologies that illustrate some of these processes, with a special focus on the study of the impact of TME acidity on the membrane permeability of several antitumor drugs.

Since my PhD in 2003 (Bern, CH), I have been working on molecular modeling and simulations, in particular, on the development of new in silico methods to deal with pH effects in biomolecules. During my pos- doc years (2003-2009) in Antonio Baptista's group (ITQB), I did a new implementation of the stochastic constant-pH MD (CpHMD) method, which was then applied to several biomolecules in the following years. Since I started my group at the Faculty of Sciences, University of Lisbon (2009), I also extended the CpHMD methodology to lipid bilayers to allow the correct modeling of the pH effects in membranes. As expected, the following step focused on the study of pH-dependent processes involving peptides interacting with lipid bilayers, which my group has explored using our state-of-the-art methodology. Currently, we are one of the very few groups in the world that can apply CpHMD methodologies to complex systems involving peptides, proteins, and drugs interacting with lipid bilayers coupled with protonation changes.

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