Project title

Adding realism to the molecular modeling of lipidic membranes: inclusion of pH effects

Scientific Coordinator's name:

Miguel Ângelo dos Santos Machuqueiro

Scientific Coordinator's e-mail:

mamachuqueiro@ciencias.ulisboa.pt

Principal R&D Unit:

Centro de Química e Bioquímica (CQB)

Other R&D Units involved in the project:

Other R&D units involved in the project

Project keyword(s)

pH effects on membranes, protonation/conformation coupling, cardiolipin, biomolecular modeling

Short abstract and comments

This project is one step forward in the direction of adding realism to the current way we model biological membranes. These membranes generally have on their surfaces negatively charged groups that give rise to a surface electrostatic potential. The negative charges come mainly from anionic lipids that are prone to protonation under the right conditions. It is not so uncommon to find this fact neglected in the literature. Many studies, both experimental and theoretical, tend to “simplify” the problem by using in their membrane models neutral (usually zwiterionic) phospholipids. In the available modeling studies on anionic and negatively charged lipids, their negative charges are fixed. This is usually justified with the fact that the pKa values are too low to allow for any (even partial) protonation. This approach can be very well compromised, to a certain level, if we take in consideration the hypothesis that biological membranes share protons as “acid-anion” dimmers and that anionic lipids thus trap and conduct protons along the headgroup domain of bilayers that contain such anionic lipids. The “acid-anion” mechanism suggests that some of these anionic lipids can retain protons at higher pH values, hence altering their structural properties. Titration studies of Cardiolipins (CL) using the developed constant-pH MD method will provide us different pKa values according to the CL type and environment in which we do the study. This data can help us understand the factors that influence CL behavior towards proton exchange. Of major importance is the acyl chain length and overall symmetry of CL. It is known that the four chains of CL are symmetrical in length and in some cases like mammalian liver mitochondria, identical. A disruption in this symmetry is associated with a known disease called the Barth’s Syndrome.

Potential uses/indications

*: knowledge of pH effects on lipidic membranes- Barth´s Syndrome