Journal of Proteomics & Bioinformatics
Open Access
ISSN: 0974-276X
ISSN: 0974-276X
Marko Sever and Franci Merzel
National Institute of Chemistry, Slovenia
Posters & Accepted Abstracts: J Proteomics Bioinform
Statement of the Problem: In our work we focus on various systems of membrane co-transporters, which are similar in their capacity to facilitate the movement of water across the cell membrane in addition to the transport of their native substrates. Mainly we focus on the sodium glucose co-transporter 1 (hSGLT1) on which we plan to develop the methodologies that will be transferred on other systems, probably LeuT homologues. Mechanism of water transport through membrane co-transporters in not fully elucidated yet. Methodology & Theoretical Orientation: We utilized explicit molecular dynamics simulations of the studied biomolecular systems. We calculated various time dependent parameters describing local structure of the water channel, including thermodynamic, electrostatic and geometric aspects. The correlations between these parameters were determined, with the final goal of better elucidating the mechanisms of water transport in these systems. The characteristic protein movements present in the systems were identified with the use of normal mode analysis. Results: By using the method of normal mode analysis in conjunction with using a projection function, we found a significant difference in the breathing character between the wild type SGLT1 and the dual mutant (F453C and Q457C) in the low frequency region. The radial component of the breathing motion is more pronounced in the dual mutant relative to the wild type which correlates with the higher water permeability found experimentally in case of dual mutant. This might indicate an importance of concerted dynamical modes in the water transport in membrane proteins. Conclusion & Significance: The studied membrane co-transporter systems are promising targets or models for drug development. Elucidating their conformational behavior in greater detail would have positive effect on drug development. Recent Publications: 1. Lehmann A and Hornby P J (2016) Intestinal SGLT1 in metabolic health and disease. American Journal of Physiology- Gastrointestinal and Liver Physiology 310(11):G887-98. 2. Zeuthen T, Gorraitz E, Her K, Wright E M and Loo D D F (2016) Structural and functional significance of water permeation through co-transporters. Proceedings of the National Academy of Sciences of the United States of America 113(44):E6887-E6894. 3. Zhu F (2014) How does Water Pass through a Sugar Transporter? Biophysical Journal 106(6):1229-1230. 4. Penmatsa A and Gouaux E (2014) How LeuT shapes our understanding of the mechanisms of sodium-coupled neurotransmitter transporters. The Journal of Physiology 592(5):863-869. 5. Robert L Dobbins, Frank L, et al., (2015) Selective sodium-dependent glucose transporter 1 inhibitors block glucose absorption and impair glucose-dependent insulinotropic peptide release. American Journal of Physiology- Gastrointestinal and Liver Physiology 308(11):G946-G954.