(1) Protein recognition and target binding in calmodulin dependent calcium signaling:

Dr. Cheung has focused on the protein folding, binding, and function of calmodulin. Calmodulin is a calcium sensing protein that encodes and transmits extracellular information in the form of varying patterns in the calcium flux. A calcium-saturated calmodulin then switches on or off a signaling pathway by binding with competing target partners. It is important to understand the principles of calmodulin’s target selection in a calcium-dependent signaling pathway, as this has great significance in the biological functions of a cell. Her computational research shows that calmodulin grossly changes its structure from an extended to a collapsed form upon binding with a target peptide that typically folds into a helix. This bound complex either weakens or strengthens calmodulin’s affinity for calcium ions depending on its stability. Her work is the first to provide a molecular insight into calmodulin’s reciprocal relation between target types and calcium binding.

1. Q. Wang, P. Zhang, L. Hoffman, S. Tripathi, D. Homouz, L. Y., N. M. Waxham and M. S. Cheung, Proc Nat Acad Sci USA. 110, 20545-20550 (2013).

2. S. Tripathi, Q. Wang, P. Zhang, L. Hoffman, M. N. Waxham and M. S. Cheung, J. Mol. Recognit. 28, 74-86 (2015).

3. S. Tripathi, M. N. Waxham, M. S. Cheung and Y. Liu, Sci. Reports 5, 14259 (2015).

4. P. Zhang, L. S. Tripathi, H. Trinh, M. S. Cheung, "Opposing intermolecular tuning of Ca2+ affinity for calmoduin by target peptide", Biop. J, 112, 1105–1119 (2017).

(2) The effect of a cellular environment on protein folding dynamics:

The macromolecular crowding effect is a result of volume exclusion from surrounding macromolecules that affect the dynamics of a polymeric biomolecule. It is known since the 1950s that the density fluctuation of the macromolecules creates a void where a protein resides and that statistically favors a compact conformation over an extended one. However, the determination of the “native” state becomes very interesting when the conformation of a compact protein is malleable and it is easily adjusted by the interactions with other objects. My group has revealed the protein-folding ensemble in a crowded environment using a combined approach of molecular modeling and computer simulations. We discovered a wide range of folding behavior in a poly disperse environment, which explains the variation of folding temperatures of a protein at different parts of a cell. We have developed meaningful protein models to address the effect of several forces, such as hydrodynamic interactions, on protein folding inside a cell.

1. D. Homouz, M. Perham, A. Samiotakis, M. S. Cheung and P. Wittung-Stafshede, Proc Natl Acad Sci U S A 105, 11754-11759 (2008).

2. A. Dhar, A. Samiotakis, S. Ebbinghaus, L. Nienhaus, D. Homouz, M. Gruebele and M. S. Cheung, Proc Nat Acad Sci USA. 107, 17586-17591 (2010).

3. Q. Wang and M. S. Cheung, Biophys. J . 102, 2353-2361 (2012).

4. F. C. Zegarra, D. Homouz, Y. Eliaz, A. G. Gasic, M.S. Cheung, “The impact of hydrodynamic interactions on protein folding rates depends on temperature”, Phys. Rev. E, 97, 032402 (2018).

(3) Explore the energy landscape of artificial photosynthetic materials in extreme conditions:

Artificial photosynthetic materials (APM) are bio-inspired materials that are designed by learning from the natural photosynthesis of plants and bacteria. APM hold great promises in providing sustainable, affordable, and renewable energy resources. One of these molecules is a light-harvesting molecular triad, a covalently linked carotenoid-porphrin-C60 compound that demonstrates an amazing ability to absorb light and to produce excited charge-separation states with a giant dipole in its linearly extended configuration. However, it is structurally flexible in solution under ambient temperature, reducing its efficiency of solar-energy conversion. There is a need for understanding the structure-function relationship of molecular triad by computer modeling and simulations. We explored its conformational distributions in solutions by using a combined approach of all-atomistic molecular dynamics simulations with explicit solvent, importance sampling, and quantum chemistry calculations of the electronic states. We found that conformation of the carotene component varies the most in both solution and in confinement. We discovered a kinetic-partitioning mechanism for charge transfer between a linearly extended conformation and bent conformations. This work shed light into a principle of design for better efficiency by populating the linearly extended conformations with solution or with surface confinement.

1. G. Su, A. Czader, D. Homouz, G. Bernardes, S. Mateen and M. S. Cheung, J. Phys. Chem. B 116, 8460-8473 (2012).

2. D. Balamurugan, A. J. A. Aquino, F. De Dios, L. Flores, H. Lischka and M. S. Cheung, J. Phys. Chem. B 117, 12065-12075 (2013).

3. A. K. Manna, D. Balamurugan, M. S. Cheung and B. D. Dunietz, J. Phys. Chem. Lett. 6, 1231–1237 (2015).

4. O.N. Starovoytov, P. Zhang, P. Cieplak, , M. S. Cheung, “Induced polarization restricts conformational distribution of a light-harvesting molecular triad in the ground state”, Phys. Chem. Chem. Phys. 19, 22969-22980 (2017).