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PhD Defense Habiburrahman Zulfikri

Computational exploration of optical and functional properties of biorelevant photoswitches

Habiburrahman Zulfikri is a PhD student in the research group Computational Chemical Physic. His supervisor is prof.dr. C. Filippi from the faculty of Science and Technology. 

Developing molecular photoswitches for applications in material science and biology is a very active field of research in chemistry. Photoswitches are a class of small molecular machines whose structures and properties can be switched between two or more states with light as a trigger. The importance of this field is marked by the awarding of the Nobel Prize in Chemistry in 2016 “for the design and synthesis of molecular machines”. In this dissertation, we contribute to the better understanding of three selected photoswitches using computational means. These photoswitches are biorelevant because they either exist in nature (commonly called chromophores) or can be covalently coupled to a biomolecular support and operated at physiological conditions.

When a photoswitch is irradiated with light at a particular wavelength, the photon energy is absorbed to promote electronic transition from an occupied to an unoccupied orbital yielding an electronic excited state. The excited state of an isomer should relax to the ground state of another isomer for a successful transformation. In Chapter 3, we develop a new class of many-body wave functions within the accurate quantum Monte Carlo (QMC) framework to explore the excited-state potential energy surfaces (PES) of photoswitches. In constructing these wave functions, we take advantage of the flexibility of QMC methods that can work with multiple sets of localized active orbitals corresponding to the different bonding pattern of the dominant Lewis resonance structures of the molecule. We also adopt the concept of orbitals domains of local coupled-cluster methods to select orbitals to correlate within an active space. The determinants are built from the domains, grouped in classes, and systematically included in the wave-function expansion. Using retinal model chromophores as prototypical test cases, we find that our novel and compact wave functions can be flexibly and accurately applied to very different parts of a PES using the same, small set of determinants. Therefore, our multi-resonance local wave functions together with the recently developed scheme for the efficient computation of interatomic forces open the possibility to efficiently compute the excited-state PES of the full retinal chromophore as well as other large photoswitches at the QMC level.

In Chapter 4, we embark on a journey to understand the complex molecular photoswitching mechanism of donor-acceptor Stenhouse adducts (DASAs). These photoswitches are relatively new and we believe that the effective and efficient development of these systems can only be achieved via a thorough understanding of the reaction mechanism in different environments. At the density functional theory level, we are able to explain the available experimental data of photoswitching of two relevant DASA molecules in a nonpolar (toluene) and a polar (methanol) solvent as regards the reversibility of the reactions, the relative rate of the ring-closure reaction in the two contrasting solvents, and the different structures of the final products. We also present a preliminary excited-state study in vacuum with multiconfigurational wave-function methods. We find that computing the excited-state PES of these systems requires a method that can account for both static and dynamical electron correlation. Furthermore, based on the existence of an excited-state minimum computed at a higher level of (perturbation-based) theory, we infer the presence of a barrier for rotation around any formal double bonds.

Finally, while the current knowledge of the reaction mechanism of spiropyran (SP) photoswitches appears to be sufficient as demonstrated by their application in many different fields, we focus our attention on understanding the very recent use of SP for drug-delivery applications in Chapter 5. Our experimental collaborators have demonstrated that, by photoswitching a single unit of spiropyran covalently connected to subdomain IA of the human serum albumin protein, one induces ligand release in the adjacent subdomain IB. Our molecular dynamics simulations elucidate

the nature of the interactions among the protein, the photoswitch, and the ligand. We find that the covalent attachment of SP weakens a key hydrogen bonds maintaining the ligand in the IB binding pocket, and that further perturbation is introduced by photoswitching SP. Furthermore, our internal dynamics analysis of the two subdomains reveals that, upon photoswitching, the binding pocket breathes more and that the motion of the two subdomains become even more decoupled. Our simulations demonstrate the allosteric nature of the interaction between the two subdomains induced by the presence of the photoswitch and provide an explanation of the factors which regulate the ligand release observed experimentally.