Mechanism by which water and protein electrostatic interactions control proton transfer at the active site of channelrhodopsin

Adam, Suliman; Bondar, Ana‐Nicoleta

doi:10.1371/journal.pone.0201298

Cited by 23 publications

(40 citation statements)

References 98 publications

(164 reference statements)

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“…The QM method during the optimization was the CAM-B3LYP method [36]. For the MM part, the CHARMM36 protein force field [37,38] and the TIP3P water model [39] were employed throughout all our computations. The Amber [40] QM/MM interface [41] was used to generate final input files from the optimized structure.…”

Section: Structural Modellingmentioning

confidence: 99%

Ultrafast Backbone Protonation in Channelrhodopsin-1 Captured by Polarization Resolved Fs Vis-pump—IR-Probe Spectroscopy and Computational Methods

et al. 2020

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Channelrhodopsins (ChR) are light-gated ion-channels heavily used in optogenetics. Upon light excitation an ultrafast all-trans to 13-cis isomerization of the retinal chromophore takes place. It is still uncertain by what means this reaction leads to further protein changes and channel conductivity. Channelrhodopsin-1 in Chlamydomonas augustae exhibits a 100 fs photoisomerization and a protonated counterion complex. By polarization resolved ultrafast spectroscopy in the mid-IR we show that the initial reaction of the retinal is accompanied by changes in the protein backbone and ultrafast protonation changes at the counterion complex comprising Asp299 and Glu169. In combination with homology modelling and quantum mechanics/molecular mechanics (QM/MM) geometry optimization we assign the protonation dynamics to ultrafast deprotonation of Glu169, and transient protonation of the Glu169 backbone, followed by a proton transfer from the backbone to the carboxylate group of Asp299 on a timescale of tens of picoseconds. The second proton transfer is not related to retinal dynamics and reflects pure protein changes in the first photoproduct. We assume these protein dynamics to be the first steps in a cascade of protein-wide changes resulting in channel conductivity.

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Section: Structural Modellingmentioning

confidence: 99%

Ultrafast Backbone Protonation in Channelrhodopsin-1 Captured by Polarization Resolved Fs Vis-pump—IR-Probe Spectroscopy and Computational Methods

et al. 2020

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“…Computational methods, particularly molecular dynamics simulations and quantum mechanics simulations, play crucial roles in understanding the role of water in the structure and function of biomacromolecules. Molecular dynamics simulations were used to understand the role of water molecules in protein–DNA binding [ 183 ], enthalpy–entropy compensation during protein–ligand interactions [ 184 ], proton transfer reactions in channel rhodopsins [ 185 ], etc. Furthermore, MD simulations were used to complement experimental methods like terahertz absorption spectroscopy [ 186 ], neutron scattering [ 187 ], and time-resolved fluorescence spectroscopy [ 34 ] to understand the structure and dynamics of folded and intrinsically disordered proteins.…”

Section: Novel Insights From Computational Methodsmentioning

confidence: 99%

Role of Computational Methods in Going beyond X-ray Crystallography to Explore Protein Structure and Dynamics

Srivastava

Nagai

Srivastava

et al. 2018

IJMS

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Protein structural biology came a long way since the determination of the first three-dimensional structure of myoglobin about six decades ago. Across this period, X-ray crystallography was the most important experimental method for gaining atomic-resolution insight into protein structures. However, as the role of dynamics gained importance in the function of proteins, the limitations of X-ray crystallography in not being able to capture dynamics came to the forefront. Computational methods proved to be immensely successful in understanding protein dynamics in solution, and they continue to improve in terms of both the scale and the types of systems that can be studied. In this review, we briefly discuss the limitations of X-ray crystallography in studying protein dynamics, and then provide an overview of different computational methods that are instrumental in understanding the dynamics of proteins and biomacromolecular complexes.

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“…41 SCC-DFTB provides a good description of biological systems containing retinal [50][51][52] and has been utilized in the past to study the impact of the retinal active-site structure on absorption and IR spectra. [53][54][55] Here, we use four of the previously generated MD trajectories: 41 two with deprotonated E162 and two with protonated. All other amino acid residues are in their standard protonation states, except for E122, E129 and D195, which we model as neutral.…”

Section: Simulation Setupmentioning

confidence: 99%

“…Several studies have shown the Schiff base in ChR to be involved in hydrogen-bonding networks containing the counterions D292/E162 and water molecules. 33,41,[98][99] Because these interactions can contribute to the opsin shift and because SCC-DFTB is able to model hydrogen-bonding networks with the same quality as full DFT with a medium-sized basis set, 45 we investigated their effect by divding our snapshots into three hydrogen-bonding patterns: The Schiff base hydrogenbonding with water only (HBw) (Figure 4a), the Schiff base hydrogen-bonding with a counterion (HBc) (either D292 or E162, Figure 4b), or the Schiff base forming a three-center hydrogen bond with water and either D292 or E162 (HBwc, Figure 4c). Figure 5a).…”

Section: Hydrogen-bonding Partners Of the Schiff Basementioning

confidence: 99%

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Structural Factors Determining the Absorption Spectrum of Channelrhodopsins: A Case Study of the Chimera C1C2

Adam

Wiebeler²,

Schapiro³

2020

Preprint

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Channelrhodopsins are photosensitive proteins that trigger flagella motion in single cell algae and have been successfully utilized in optogenetic applications. In optogenetics light is used to activate neural cells in living organisms, which can be achieved by exploiting the ion channel signaling of channelrhodopsins. Tailoring channelrhodopsins for such applications includes the tuning of the absorption maximum. In order to establish rational design and to obtain a desired spectral shift, a basic understanding of the absorption spectrum is required. We have studied the chimera C1C2 as a representative of this protein family and the first member with an available crystal structure. For this purpose, we sampled the conformations of C1C2 using QM/MM molecular dynamics, and subjected the resulting snapshots of the trajectory to excitation energy calculations using ADC(2) and simplified TD-DFT. In contrast to previous reports, we found that different hydrogen-bonding networks—involving the retinal protonated Schiff base, the putative counterions E162 and D292 as well as water molecules—had only a small impact on the absorption spectrum. However, in case of deprotonated E162 increasing the distance to the Schiff base hydrogen-bonding partner led to a systematic blue shift. The β-ionone ring rotation was identified as another important contributor. Yet the most important factor was found to be the bond length alternation and bond order alternation that were linearly correlated to the absorption maximum by up to 62 % and 82 %, respectively. We ascribe this novel insight into the structural basis of the absorption spectrum to our enhanced protein setup that includes membrane embedding as well as long and extensive sampling.

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Mechanism by which water and protein electrostatic interactions control proton transfer at the active site of channelrhodopsin

Cited by 23 publications

References 98 publications

Ultrafast Backbone Protonation in Channelrhodopsin-1 Captured by Polarization Resolved Fs Vis-pump—IR-Probe Spectroscopy and Computational Methods

Ultrafast Backbone Protonation in Channelrhodopsin-1 Captured by Polarization Resolved Fs Vis-pump—IR-Probe Spectroscopy and Computational Methods

Role of Computational Methods in Going beyond X-ray Crystallography to Explore Protein Structure and Dynamics

Structural Factors Determining the Absorption Spectrum of Channelrhodopsins: A Case Study of the Chimera C1C2

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