Engineering the vibrational coherence of vision into a synthetic molecular device

The light-induced double-bond isomerization of the visual pigment rhodopsin operates a molecular-level optomechanical energy transduction, which triggers a crucial protein structure change. In fact, rhodopsin isomerization occurs according to a unique, ultrafast mechanism that preserves mode-specific vibrational coherence all the way from the reactant excited state to the primary photoproduct ground state. The engineering of such an energy-funnelling function in synthetic compounds would pave the way towards biomimetic molecular machines capable of achieving optimum light-to-mechanical energy conversion. Here we use resonance and off-resonance vibrational coherence spectroscopy to demonstrate that a rhodopsin-like isomerization operates in a biomimetic molecular switch in solution. Furthermore, by using quantum chemical simulations, we show why the observed coherent nuclear motion critically depends on minor chemical modifications capable to induce specific geometric and electronic effects. This finding provides a strategy for engineering vibrationally coherent motions in other synthetic systems

Impact of Electronic State Mixing on the Photoisomerization Timescale of Natural and Synthetic Molecular Systems

The need for a detailed mechanistic understanding of the photoisomerization of retinal chromophore (retinal protonated Schiff base, rPSB) is becoming increasingly important, not only due to its fundamental importance in vision but also owing to the growing number of applications in various fields. The development of microbial rhodopsin based fluorescent probes and actuators essential in neuroscience, synthetic bio-mimetic molecular switches and motors useful in material science and synthetic biology are examples of such applications. The work presented in this dissertation is devoted to unveil and understand a novel mechanistic factor with significant impact on the photoisomerization of rPSB-like systems. This factor corresponds to the interaction between the first electronic excited state and higher states (usually the second excited state) occurring during the excited state lifetime or, in other words, along the excited state photoisomerization coordinate. This electronic state mixing effect is studied by employing different computer tools including hybrid quantum mechanics/molecular mechanics (QM/MM) methods. The investigated systems include representative animal and microbial rhodopsins, bio-mimetic N-alkyl-indanylidene-pyrrolinium (NAIP) molecular switches and a recently reported water soluble rhodopsin mimic. Our results unveil two type of effects due to changes in the electronic mixing: an impact on the excited state lifetime and an impact on vibrational coherence as we now briefly describe. The impact on excited state lifetime is first demonstrated by uncovering the variation of rPSB photoisomerization speed in different environments is due to an increase or decrease of electronic state mixing and that this effect can be controlled by the electrostatic field of the environment. This leads us to hypothesize that animal rhodopsins, which isomerize within 200 fs, have been evolved to minimize the electronic state mixing such that biological functions are carried out in a timely manner. We then show that electronic state mixing can be used as a design principle to achieve artificial rPSBs with a longer excited state lifetime useful for producing rhodopsin based fluorescent probes. In this context, we demonstrate that minor electron donating or withdrawing chemical substitutions can cause an increase or decrease in the photoisomerization speed of rPSB. We have also investigated the photocycle and the electronic state mixing of a water-soluble artificial rhodopsin mimic. The room temperature photodynamics simulations of this system suggests that molecules of a light excited population which decay early or later is possibly modulated by electronic state mixing. The impact of electronic state mixing on vibrational coherence is mainly investigated focusing on synthetic molecular switches. Accordingly, we show how electronic state mixing induced by steric effects can be used to control the vibrational coherence of NAIP molecular switches. On this basis, we propose that vibrational coherence may be engineered into other synthetic molecular devices by modulating steric and electronic effects

Impact of Electronic State Mixing on the Photoisomerization Timescale of Natural and Synthetic Molecular Systems

The need for a detailed mechanistic understanding of the photoisomerization of retinal chromophore (retinal protonated Schiff base, rPSB) is becoming increasingly important, not only due to its fundamental importance in vision but also owing to the growing number of applications in various fields. The development of microbial rhodopsin based fluorescent probes and actuators essential in neuroscience, synthetic bio-mimetic molecular switches and motors useful in material science and synthetic biology are examples of such applications. The work presented in this dissertation is devoted to unveil and understand a novel mechanistic factor with significant impact on the photoisomerization of rPSB-like systems. This factor corresponds to the interaction between the first electronic excited state and higher states (usually the second excited state) occurring during the excited state lifetime or, in other words, along the excited state photoisomerization coordinate. This electronic state mixing effect is studied by employing different computer tools including hybrid quantum mechanics/molecular mechanics (QM/MM) methods. The investigated systems include representative animal and microbial rhodopsins, bio-mimetic N-alkyl-indanylidene-pyrrolinium (NAIP) molecular switches and a recently reported water soluble rhodopsin mimic. Our results unveil two type of effects due to changes in the electronic mixing: an impact on the excited state lifetime and an impact on vibrational coherence as we now briefly describe. The impact on excited state lifetime is first demonstrated by uncovering the variation of rPSB photoisomerization speed in different environments is due to an increase or decrease of electronic state mixing and that this effect can be controlled by the electrostatic field of the environment. This leads us to hypothesize that animal rhodopsins, which isomerize within 200 fs, have been evolved to minimize the electronic state mixing such that biological functions are carried out in a timely manner. We then show that electronic state mixing can be used as a design principle to achieve artificial rPSBs with a longer excited state lifetime useful for producing rhodopsin based fluorescent probes. In this context, we demonstrate that minor electron donating or withdrawing chemical substitutions can cause an increase or decrease in the photoisomerization speed of rPSB. We have also investigated the photocycle and the electronic state mixing of a water-soluble artificial rhodopsin mimic. The room temperature photodynamics simulations of this system suggests that molecules of a light excited population which decay early or later is possibly modulated by electronic state mixing. The impact of electronic state mixing on vibrational coherence is mainly investigated focusing on synthetic molecular switches. Accordingly, we show how electronic state mixing induced by steric effects can be used to control the vibrational coherence of NAIP molecular switches. On this basis, we propose that vibrational coherence may be engineered into other synthetic molecular devices by modulating steric and electronic effects

Electronic State Mixing Controls the Photoreactivity of a Rhodopsin with all- trans Chromophore Analogues

Rhodopsins hosting synthetic retinal protonated Schiff base analogues are important for developing tools for optogenetics and high-resolution imaging. The ideal spectroscopic properties of such analogues include long-wavelength absorption/emission and fast/hindered photoisomerization. While the former may be achieved, for instance, by elongating the chromophore π-system, the latter requires a detailed understanding of the substituent effects (i.e., steric or electronic) on the chromophore light-induced dynamics. In the present letter we compare the results of quantum mechanics/molecular mechanics excited-state trajectories of native and analogue-hosting microbial rhodopsins from the eubacterium Anabaena. The results uncover a relationship between the nature of the substituent on the analogue (i.e., electron-donating (a Me group) or electron-withdrawing (a CF3 group)) and rhodopsin excited-state lifetime. Most importantly, we show that electron-donating or -withdrawing substituents cause a decrease or an increase in the electronic mixing of the first two excited states which, in turn, controls the photoisomerization speed

Geometry Optimization: A Comparison of Different Open-Source Geometry Optimizers

Based on a series of energy minimizations with starting structures obtained from the Baker test set of 30 organic molecules, a comparison is made between various open-source geometry optimization codes that are interfaced with the open-source QUantum Interaction Computational Kernel (QUICK) program for gradient and energy calculations. The findings demonstrate how the choice of the coordinate system influences the optimization process to reach an equilibrium structure. With fewer steps, internal coordinates outperform Cartesian coordinates while the choice of the initial Hessian and Hessian update method in quasi-Newton approaches made by different optimization algorithms also contributes to the rate of convergence. Furthermore, an available open-source machine learning method based on Gaussian Process Regression (GPR) was evaluated for energy minimizations over surrogate potential energy surfaces with both Cartesian and internal coordinates, with internal coordinates outperforming Cartesian. Overall, geomeTRIC and DL-FIND with their default optimization method as well as with GPR-based model using Hartree--Fock theory with the 6-31G** basis set, needed a comparable number of geometry optimization steps to the approach of Baker using a unit matrix as the initial Hessian to reach the optimized geometry. On the other hand, the Berny and Sella offerings in ASE outperformed the other algorithms. Based on this we recommend using the file-based approaches, ASE/Berny and ASE/Sella, for large-scale optimization efforts, while if using a single executable is preferable, we now distribute QUICK integrated with DL-FIND

Open-Source Multi-GPU-Accelerated QM/MM Simulations with AMBER and QUICK

The quantum mechanics/molecular mechanics (QM/MM) approach is an essential and well-established tool in computational chemistry that has been widely applied in a myriad of biomolecular problems in the literature. In this publication, we report the integration of the QUantum Interaction Computational Kernel (QUICK) program as an engine to perform electronic structure calculations in QM/MM simulations with AMBER. This integration is available through either a file-based interface (FBI) or an application programming interface (API). Since QUICK is an open-source GPU-accelerated code with multi-GPU parallelization, users can take advantage of “free of charge” GPU-acceleration in their QM/MM simulations. In this work, we discuss implementation details and give usage examples. We also investigate energy conservation in typical QM/MM simulations performed at the microcanonical ensemble. Finally, benchmark results for two representative systems, the N-methylacetamide (NMA) molecule and the photoactive yellow protein (PYP) in bulk water, show the performance of QM/MM simulations with QUICK and AMBER using a varying number of CPU cores and GPUs. Our results highlight the acceleration obtained from a single or multiple GPUs; we observed speedups of up to 38x between a single GPU vs. a single CPU core and of up to 2.6x when comparing four GPUs to a single GPU. Results also reveal speedups of up to 3.5x when the API is used instead of FBI.</div

Comparative Quantum-Classical Dynamics of Natural and Synthetic Molecular Rotors Show How Vibrational Synchronization Modulates the Photoisomerization Quantum Efficiency

We use quantum-classical trajectories to investigate the origin of the different photoisomerization quantum efficiency observed in the dim-light visual pigment Rhodopsin and in the light-driven biomimetic molecular rotor para-methoxy N-methyl indanylidene-pyrrolinium (MeO-NAIP) in methanol. The results reveal that effective light-energy conversion requires, in general, an auxiliary molecular vibration (called promoter) that does not correspond to the rotary motion but that synchronizes with it at specific times. They also reveal that Nature has designed Rhodopsin to exploit two mechanisms working in a vibrationally coherent regime. The first uses a wag promoter to ensure that ca. 75% of the absorbed photons lead to unidirectional rotations. The second mechanism ensures that the same process is fast enough to avoid directional randomization. It is found that MeO-NAIP in methanol is incapable of exploiting the above mechanisms resulting into a 50% quantum efficiency loss. However, when the solvent is removed, MeO-NAIP rotation is predicted to synchronize with a ring-inversion promoter leading to a 30% increase of quantum efficiency and, therefore, biomimetic behavior

Parallel Implementation of Density Functional Theory Methods in the Quantum Interaction Computational Kernel Program

We present the details of a GPU capable exchange correlation (XC) scheme integrated into the open source QUantum Interaction Computational Kernel (QUICK) program. Our implementation features an octree based numerical grid point partitioning scheme, GPU enabled grid pruning and basis/primitive function prescreening and fully GPU capable XC energy and gradient algorithms. Benchmarking against the CPU version demonstrated that the GPU implementation is capable of delivering an impres- sive performance while retaining excellent accuracy. For small to medium size protein/organic molecular systems, the realized speedups in double precision XC energy and gradient computation on a NVIDIA V100 GPU were 60 to 80-fold and 140 to 780- fold respectively as compared to the serial CPU implementation. The acceleration gained in density functional theory calculations from a single V100 GPU significantly exceeds that of a modern CPU with 40 cores running in parallel. </div

QM/MM Simulations on NVIDIA and AMD GPUs

We have ported and optimized the GPU accelerated QUICK and AMBER based ab initio QM/MM implementation on AMD GPUs. This encompasses the entire Fock matrix build and force calculation in QUICK including one-electron integrals, two-electron repulsion integrals, exchange-correlation quadrature, and linear algebra operations. General performance improvements to the QUICK GPU code are also presented. Benchmarks carried out on NVIDIA V100 and AMD MI100 cards display similar performance on both hardware for standalone HF/DFT calculations with QUICK and QM/MM molecular dynamics simulations with QUICK/AMBER. Furthermore, with respect to the QUICK/AMBER release version 21, significant speedups are observed for QM/MM molecular dynamics simulations. This significantly increases the range of scientific problems that can be addressed with open-source QM/MM software on state-of-the-art computer hardware

Quantum–classical simulations of rhodopsin reveal excited-state population splitting and its effects on quantum efficiency

International audienceThe activation of rhodopsin, the light-sensitive G-protein-coupled receptor responsible for dim-light vision in vertebrates, is driven by an ultrafast excited-state double-bond isomerization with a quantum efficiency of almost 70%. The origin of such light sensitivity is not understood and a key question is whether in-phase nuclear motion controls the quantum efficiency value. In this study we used hundreds of quantum-classical trajectories to show that, 15 fs after light absorption, a degeneracy between the reactive excited state and a neighbouring state causes the splitting of the rhodopsin population into subpopulations. These subpopulations propagate with different velocities and lead to distinct contributions to the quantum efficiency. We also show here that such splitting is modulated by protein electrostatics, thus linking amino acid sequence variations to quantum efficiency modulation. Finally, we discuss how such a linkage that in principle could be exploited to achieve higher quantum efficiencies would simultaneously increase the receptor thermal noise leading to a trade-off that may have played a role in rhodopsin evolution