Retinal Chromophore In Rhodopsin Research Articles

Tensor-Train Split-Operator KSL (TT-SOKSL) Method for Quantum Dynamics Simulations.

Numerically exact simulations of quantum reaction dynamics, including nonadiabatic effects in excited electronic states, are essential to gain fundamental insights into ultrafast chemical reactivity and rigorous interpretations of molecular spectroscopy. Here, we introduce the tensor-train split-operator KSL (TT-SOKSL) method for quantum simulations in tensor-train (TT)/matrix product state (MPS) representations. TT-SOKSL propagates the quantum state as a tensor train using the Trotter expansion of the time-evolution operator, as in the tensor-train split-operator Fourier transform (TT-SOFT) method. However, the exponential operators of the Trotter expansion are applied using a rank-adaptive TT-KSL scheme instead of using the scaling and squaring approach as in TT-SOFT. We demonstrate the accuracy and efficiency of TT-SOKSL as applied to simulations of the photoisomerization of the retinal chromophore in rhodopsin, including nonadiabatic dynamics at a conical intersection of potential energy surfaces. The quantum evolution is described in full dimensionality by a time-dependent wavepacket evolving according to a two-state 25-dimensional model Hamiltonian. We find that TT-SOKSL converges faster than TT-SOFT with respect to the maximally allowed memory requirement of the tensor-train representation and better preserves the norm of the time-evolving state. When compared to the corresponding simulations based on the TT-KSL method, TT-SOKSL has the advantage of avoiding the need to construct the matrix product state Laplacian by exploiting the linear scaling of multidimensional tensor-train Fourier transforms.

Steady State Photoisomerization Quantum Yield of Model Rhodopsin: Insights from Wavepacket Dynamics?

We simulate the nonequilibrium steady state cis-trans photoisomerization of retinal chromophore in rhodopsin on the basis of a two-state, two-mode model coupled to a thermal environment. By analyzing the systematic trends within an inhomogeneously broadened ensemble of systems, we find that the steady state reaction quantum yield (QY) correlates strongly with the excess energy above the crossing point of the system, in agreement with the prediction of the short-time dynamical wavepacket picture. However, the nontrivial dependence of the QY on the system-environment interaction indicates that a pure dynamical picture is insufficient and that environment-induced partial internal energy redistribution takes place before the reaction concludes. These results imply that a proper treatment of the photoisomerization reaction, particularly its high QY, must account for the redistribution and dissipation of energy beyond the dynamical wavepacket motion that is typically employed in the literature and that is appropriate only in the transient regime.

Extreme Parametric Sensitivity in the Steady-State Photoisomerization of Two-Dimensional Model Rhodopsin

We computationally studied the photoisomerization reaction of the retinal chromophore in rhodopsin using a two-state two-mode model coupled to thermal baths. Reaction quantum yields at the steady state (10 ps and beyond) were found to be considerably different than their transient values, suggesting a weak correlation between transient and steady-state dynamics in these systems. Significantly, the steady-state quantum yield was highly sensitive to minute changes in system parameters, while transient dynamics was nearly unaffected. Correlation of such sensitivity with standard level spacing statistics of the nonadiabatic vibronic system suggests a possible origin in quantum chaos. The significance of this observation of quantum yield parametric sensitivity in biological models of vision has profound conceptual and fundamental implications.

The origin of absorptive features in the two-dimensional electronic spectra of rhodopsin.

In rhodopsin, the absorption of a photon causes the isomerization of the 11-cis isomer of the retinal chromophore to its all-trans isomer. This isomerization is known to occur through a conical intersection (CI) and the internal conversion through the CI is known to be vibrationally coherent. Recently measured two-dimensional electronic spectra (2DES) showed dramatic absorptive spectral features at early waiting times associated with the transition through the CI. The common two-state two-mode model Hamiltonian was unable to elucidate the origin of these features. To rationalize the source of these features, we employ a three-state three-mode model Hamiltonian where the hydrogen out-of plane (HOOP) mode and a higher-lying electronic state are included. The 2DES of the retinal chromophore in rhodopsin are calculated and compared with the experiment. Our analysis shows that the source of the observed features in the measured 2DES is the excited state absorption to a higher-lying electronic state and not the HOOP mode.

Nonadiabatic dynamics and photoisomerization of biomimetic photoswitches

N-alkylated indanylidene pyrroline Schiff bases (NAIPs) are of great interest because their photoisomerization mimics the primary photoreactions of the retinal chromophore in rhodopsin. The nonadiabatic dynamics of two NAIP models (OMe-NAIP and dMe-OMe-NAIP) are investigated by trajectory surface-hopping method at the semi-empirical OM2/MRCI level. Both molecules show ultrafast isomerization governed by nonadiabatic dynamics via the S0/S1 conical intersections (CIs). Two CIs, CIα and CIβ, play important roles in the E→Z and Z→E isomerization dynamics, respectively, and are mainly distinguished by different twisting statuses of the central C1′–C4 double bond. Although both compounds show ultrafast nonadiabatic dynamics, the S1 lifetime of dMe-OMe-NAIP is much longer than that of OMe-NAIP. By removing the methyl group, dMe-OMe-NAIP allows less twist at the C1′–C4 double bond than OMe-NAIP. This result in the slower excited-state decay of dMe-OMe-NAIP, providing solid evidence to support a similar hypothesis proposed in a previous study.

Mode-specificity of vibrationally coherent internal conversion in rhodopsin during the primary visual event.

Conical intersections play a crucial role in photochemical processes, but limited experimental information exists on the structural distortions that couple electronic with reactive nuclear motion. Using ultra-broadband and highly time-resolved optical spectroscopy, we follow the evolution of vibrational wavepackets after passage through a conical intersection during the primary visual event, the 11-cis to all-trans photoisomerization of the retinal chromophore in rhodopsin. Comparison of nuclear coherences generated under resonant and off-resonant impulsive excitation conclusively reveals coherent wavepacket motion in the bathorhodopsin photoproduct over the full vibrational manifold. We observe strongly enhanced coherences in low-frequency torsional degrees of freedom over the fingerprint region and almost complete suppression of some hydrogen wagging motion. Our ability to monitor the multidimensional evolution of nuclear wavepackets across multiple electronic states is a general means for studying the structural and dynamic origins of efficient photochemistry and provides critical experimental information for theoretical studies.

Toward an Understanding of the Retinal Chromophore in Rhodopsin Mimics

Recently, a rhodopsin protein mimic was constructed by combining mutants of the cellular retinoic acid binding protein II (CRABPII) with an all-trans retinal chromophore. Here, we present a combined computational quantum mechanics/molecular mechanics (QM/MM) and experimental ultrafast kinetic study of CRABPII. We employ the QM/MM models to study the absorption (λ(a)max), fluorescence (λ(f)max), and reactivity of a CRABPII triple mutant incorporating the all-trans protonated chromophore (PSB-KLE-CRABPII). We also study the spectroscopy of the same mutant incorporating the unprotonated chromophore and of another double mutant incorporating the neutral unbound retinal molecule held inside the pocket. Finally, for PSB-KLE-CRABPII, stationary fluorescence spectroscopy and ultrafast transient absorption spectroscopy resolved two different evolving excited state populations which were computationally assigned to distinct locally excited and charge-transfer species. This last species is shown to evolve along reaction paths describing a facile isomerization of the biologically relevant 11-cis and 13-cis double bonds. This work represents a first exploratory attempt to model and study these artificial protein systems. It also indicates directions for improving the QM/MM models so that they could be more effectively used to assist the bottom-up design of genetically encodable probes and actuators employing the retinal chromophore.

Rhodopsin Absorption from First Principles: Bypassing Common Pitfalls.

Bovine rhodopsin is the most extensively studied retinal protein and is considered the prototype of this important class of photosensitive biosystems involved in the process of vision. Many theoretical investigations have attempted to elucidate the role of the protein matrix in modulating the absorption of retinal chromophore in rhodopsin, but, while generally agreeing in predicting the correct location of the absorption maximum, they often reached contradicting conclusions on how the environment tunes the spectrum. To address this controversial issue, we combine here a thorough structural and dynamical characterization of rhodopsin with a careful validation of its excited-state properties via the use of a wide range of state-of-the-art quantum chemical approaches including various flavors of time-dependent density functional theory (TDDFT), different multireference perturbative schemes (CASPT2 and NEVPT2), and quantum Monte Carlo (QMC) methods. Through extensive quantum mechanical/molecular mechanical (QM/MM) molecular dynamics simulations, we obtain a comprehensive structural description of the chromophore-protein system and sample a wide range of thermally accessible configurations. We show that, in order to obtain reliable excitation properties, it is crucial to employ a sufficient number of representative configurations of the system. In fact, the common use of a single, ad hoc structure can easily lead to an incorrect model and an agreement with experimental absorption spectra due to cancelation of errors. Finally, we show that, to properly account for polarization effects on the chromophore and to quench the large blue-shift induced by the counterion on the excitation energies, it is necessary to adopt an enhanced description of the protein environment as given by a large quantum region including as many as 250 atoms.

Photoisomerization Control Mechanisms in Protonated Schiff Bases

We have performed ab initio excited-state molecular dynamics simulations of an isolated photo-excited protonated Schiff base (C1-N2=C3-C4=C5-C6) to search for mechanisms that control its photoisomerization outcome, such as the bond selectivity and (trans, cis) conformation. We observe that the photo-excited molecule twists around the N2C3 bond (∼80% cases of the thermal ensemble) or the C4C5 bond, and relaxes back to the ground electronic state with either a trans or cis outcome. First, we show that a significant initial distortion of several selected dihedral angles can preferentially guide the excited-state dynamics towards twisting of the C4C5 bond. Next, we examine if the bond selectivity can be controlled by the vibrational pre-excitation of the molecule along individual normal modes. We find that pre-excitation of only one of the modes, which contains a prominent propelling motion of the C4C5 bond with respect to the neighboring C3C4 single bond, leads to twisting of the C4C5 bond. Normal mode decomposition of the ground state thermal ensemble shows that in starting structures in which this same mode is pre-excited by 1-2 kBT thermal energy, the twisting of C4C5 occurs with a 30-50% probability. Finally, we find that the (trans, cis) outcome of the reaction can be controlled by selective pre-twisting of several dihedral angles, while keeping other degrees of freedom thermally excited. This choice was justified by the observed pre-twisting of retinal chromophore in rhodopsin, which exhibits 65% cis to trans transition. In the thermal ensemble with such pre-twisted dihedrals, we observe on the excited state potential energy surface synchronized twisting of CN2C3C and HN2C3H torsional angles surrounding the isomerizing N2C3 bond, which significantly increases the fraction of reactive (cis to trans) trajectories. These observations provide crucial understanding of natural photoisomerization mechanisms and their potential use in synthetic molecules.

Electrostatic Control of the Photoisomerization Efficiency and Optical Properties in Visual Pigments: On the Role of Counterion Quenching

Hybrid QM(CASPT2//CASSCF/6-31G*)/MM(Amber) computations have been used to map the photoisomerization path of the retinal chromophore in Rhodopsin and explore the reasons behind the photoactivity efficiency and spectral control in the visual pigments. It is shown that while the electrostatic environment plays a central role in properly tuning the optical properties of the chromophore, it is also critical in biasing the ultrafast photochemical event: it controls the slope of the photoisomerization channel as well as the accessibility of the S(1)/S(0) crossing space triggering the ultrafast decay. The roles of the E113 counterion, the E181 residue, and the other amino acids of the protein pocket are explicitly analyzed: it appears that counterion quenching by the protein environment plays a key role in setting up the chromophore's optical properties and its photochemical efficiency. A unified scenario is presented that discloses the relationship between spectroscopic and mechanistic properties in rhodopsins and allows us to draw a solid mechanism for spectral tuning in color vision pigments: a tunable counterion shielding appears as the elective mechanism for L<-->M spectral modulation, while a retinal conformational control must dictate S absorption. Finally, it is suggested that this model may contribute to shed new light into mutations-related vision deficiencies that opens innovative perspectives for experimental biomolecular investigations in this field.

Bond torsion affects the product distribution in the photoreaction of retinal model chromophores

Ab initio molecular dynamics (MD) calculations have been performed to study the photoisomerization of a 3-double-bond retinal model chromophore, the all-trans-4, 6-dimethylpenta-3, 5-dieniminium cation, and the possible influence of non-planar distortions on the product distribution. In total, 171 trajectories have been generated for four different conformations of the structure, a planar one and three in which the C4-C5 and the C5=C6 bonds were increasingly twisted out of plane. Starting geometries randomly distributed about the equilibrium geometry were generated by zero-point energy sampling; trajectories were calculated using CASSCF-BOMD methodology and were followed until the photoproduct and its configuration could be assigned. For the latter, two different approaches were applied, one involving the CASSCF configuration vectors, the other an analysis of the MD at the first possible hopping event. Isomerization was found to occur almost exclusively about the central C3=C4 double bond in the case of the planar model compound. Twisting the conjugated pi-system shifts the isomerization site from the central double bond to the terminal C5=C6 double bond. With both the C4-C5 and the C5=C6 bonds twisted by 20 degrees, about 35% of the trajectories lead to the configurationally inverted 5-cis product. The results are discussed with reference to the highly selective and efficient photo-induced isomerization of the retinal chromophore in rhodopsin.

Retinal versus 13-demethyl-retinal inside the rhodopsin binding pocket—a QM/MM Study§

To probe the effect of the protein environment on the retinal chromophore of rhodopsin, we performed molecular dynamics simulations using combined quantum mechanics/molecular mechanics (QM/MM). The starting geometry of the protein is based on the 2.6Å X-ray structure of bovine rhodopsin of Okada et al. [T. Okada, et al. Proc. Natl. Acad. Sci. USA 99 5982 (2002)]. The wild-type chromophore of rhodopsin according to our calculations shows a highly twisted conformation around the central region, from C10 to C13, due to non-bonded interaction with the protein pocket. The absolute sense of twist of the C11–C12 and C12–C13 bonds is negative (−19 ± 9°) and positive (170 ± 8°), respectively. The 13-demethyl retinal chromophore, in which the methyl group at the C13 position is removed, is less distorted in this region. The C11–C12 bond is less twisted (−15 ± 10°) and the C12–C13 bond is planar (179 ± 9°) . The flattened geometry of this artificial chromophore is supported by spectroscopic evidence.

Model Study of Coherent-Control of the Femtosecond Primary Event of Vision

A bichirped coherent-control scenario is introduced and implemented in a model study of coherent-control of the cis/trans photoisomerization of the retinal chromophore in rhodopsin. The approach involves selective photoexcitation of multiple vibrationally coherent wave packets by using two chirped femtosecond pulses. Control over product yields at finite time after photoexcitation of the system is achieved by externally changing the relative phases of the photoexcitation pulses and consequently affecting the interference phenomena between individual wave packet components. Furthermore, a measure of decoherence associated with the underlying quantum reaction dynamics is computed. Extensive coherent-control over transient populations is predicted, despite the ultrafast decoherence phenomena induced by the vibronic activity, providing results of broad theoretical and experimental interest.

Thr94 and Wat2b effect protonation of the retinal chromophore in rhodopsin.

Only with the help from (little) “friends” is it possible for the 11-cis-retinal Schiff base to compete successfully against Glu 113 for a proton (see picture). A strategically placed amino acid, Thr 94, plus a water molecule are sufficient to reduce the basicity of the glutamate and stabilize the protonated chromophore—this is the result of ab initio optimization and molecular-dynamic study of the retinal binding site in rhodopsin.

The Light Shall Show the Way-Or: The Conformational Changes of the Retinal Chromophore in Rhodopsin upon Light Activation.

The visual pigment rhodopsin constitutes the interface between the physical event of light absorption and the biochemical process of visual transduction within the photoreceptor cells. The signal transduction is initiated by an 11-cis→all-trans photoisomerization of the retinal chromophore of rhodopsin which causes a series of thermally driven conformational changes of the chromophore and the protein moiety. A rhodopsin conformation is generated which allows interaction with a heterotrimeric G-protein. Two recent publications follow the chromophore motions after light absorption by cross-linking experiments and by solid-state NMR spectroscopy.

Inherent chirality of the retinal chromophore in rhodopsin—A nonempirical theoretical analysis of chiroptical data

Inherent chirality of the retinal chromophore in rhodopsin—A nonempirical theoretical analysis of chiroptical data

Enantioselective binding of an 11-cis-locked cyclopropyl retinal. The conformation of retinal in bovine rhodopsin.

[formula: see text] The conformation of the retinal chromophore in rhodopsin is central for understanding the visual transduction process. The absolute twist around the 12-s bond of the chromophore in rhodopsin has been determined by studies with 11-cis-locked 11,12-cyclopropylretinal analogues (11S,12R)-2 and (11R,12S)-3, enantioselectively synthesized with the aid of an enzyme. The finding that enantiomer 2 binds to opsin while the other 3 does not defines the absolute sense of twist around the 12-s bond.

Absolute Sense of Twist of the C12-C13 Bond of the Retinal Chromophore in Rhodopsin—Semiempirical and Nonempirical Calculations of Chiroptical Data

The sign of the dihedral angle of the 12-s-trans bonds in the protonated Schiff base of 11-cis-retinal (see picture on the right) correlates with the sign of the long-wavelength absorption in the circular dichroism spectra. This is the result of the high-quality excited-state calculations on the chromophore of the visual pigment rhodopsin.

The C5H6NH2+ Protonated Shiff Base: An ab Initio Minimal Model for Retinal Photoisomerization

The minimum energy path for photoisomerization of the minimal retinal protonated Shiff base model tZt-penta-3,5-dieniminium cation (cis-C5H6NH2+) is computed using MC−SCF and multireference Moller−Plesset methods. The results show that, upon excitation to the spectroscopic state, this molecule undergoes a barrierless relaxation toward a configuration where the excited and ground states are conically intersecting. The intersection point has a ∼80° twisted central double bond which provides a route for fully efficient nonadiabatic cis → trans isomerization. This mechanism suggests that cis-C5H6NH2+ provides a suitable “ab initio” model for rationalizing the observed “ultrafast” (sub-picosecond) isomerization dynamics of the retinal chromophore in rhodopsin. The detailed analysis of the computed reaction coordinate provides information on the changes in molecular structure and charge distribution along the isomerization path. It is shown that the initial excited state motion is dominated by stretching modes ...

NMR Constraints on the Location of the Retinal Chromophore in Rhodopsin and Bathorhodopsin

ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNMR Constraints on the Location of the Retinal Chromophore in Rhodopsin and BathorhodopsinMay Han and Steven O. SmithCite this: Biochemistry 1997, 36, 23, 7280Publication Date (Web):June 10, 1997Publication History Published online10 June 1997Published inissue 1 June 1997https://doi.org/10.1021/bi975005wCopyright © 1997 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views177Altmetric-Citations5LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (12 KB) Get e-Alerts Get e-Alerts