Maity S , Ilieva N , Laio A , Torre V , Mazzolini M .

	Figure 1-AFM image of membrane patches from the rod OS disc and the plasma membrane (a) AFM topography from rod OS disc membrane showing the organization of rhodopsin in the single layered disc membrane. (b) AFM topography from rod OS plasma membrane. (c,d) Clusterization of the images in panel a and b according to their height ranges from 1–2.9 nm (area with red color) and 3–7 nm (area with green color), respectively. (e) Superposition of histograms of height profile from all the detected particles as in panel c from the images taken from rod OS disc membrane in different experiments, with a mean protrusion of 1.5 ± 0.4 nm (n = 18). (f) Superposition of histograms of height profile from all the detected particles as in panel d, from the images taken from rod OS plasma membrane in different experiments, with two different protrusions: height profile of 1.5 ± 0.7 nm and 4.9 ± 0.9 (n = 22).
	Future 2-Identification of the spatial organization of CNG channels in the rod OS plasma membrane. (a) Selected membrane patch from the base of rod OS showing different topographical features. Acquisition of images at different times demonstrates stable (blue arrows) and unstable (green arrows) features. (b) High resolution image with protrusions from the lipid bilayer with different height; 1,2,3 are CNG channels while 4,5 are rhodopsin. (c) F-D curves obtained after pulling of selected protrusion (see numbered circles). (d) Superimposition of histograms of normalized counts/bin against Lc from 29 F-D curves (in red) of CNGA1 subunit from rod OS plasma membrane, and 157 F-D curves (in grey) of CNGA1 from oocyte plasma membrane.
	Figure 3-Single molecule unfolding of CNGA1 subunit in the closed and open states. (a) Superposition of 157 F-D curves (black lines) from oocyte plasma membrane overexpressing CNGA1 channels (modified from ref.7) and a single F-D curve of CNGA1 subunit (red trace) from rod OS plasma membrane, both in the absence of cGMP (closed state). (b) Representative F-D curves of CNGA1 subunit from rod OS plasma membrane; curves 1 and 2 are full length unfolding of CNGA1single subunit with an Lc value around 272 nm, while curves 3 and 4 are unfolding of a single CNGA1 subunit pulled up to S1 transmembrane domain with an Lc value around 231 nm. (c) Superposition of 36 F-D curves of CNGA1 subunit from rod OS plasma membrane in the absence of cGMP (closed state); continuous black lines are obtained from the fitting with WLC model and numbers indicate the corresponding values of Lc. (d) The same as in c but in the presence of 2 mM cGMP (open state). (e) Histogram of normalized counts/bin against Lc obtained from all the traces in panel c (bin-3 nm); numbers represent the corresponding Lc (mean±S.D, n = 36) values in nm and the relative probability (P): five force peaks with values of Lc equal to 114 ± 4, 153 ± 3, 186 ± 4, 229 ± 6, and 273 ± 5 nm; the frequency of occurrence is 0.98, 0.98, 1, 1.00, and 0.21, respectively, with an unfolding force of 95 ± 45 pN; number in red represents the characteristic peaks for CNGA1 channels in the closed state. In roman numerals the numbers of force peaks. (f) The same as in e but for all the traces in panel d; numbers in blue represent the characteristic peaks for CNGA1 channels in the open state: eight force peaks with Lc of 48 ± 2, 84 ± 2, 113 ± 3, 140 ± 3, 172 ± 3, 191 ± 5, 234 ± 4, and 276 ± 6 nm (n = 34), and higher unfolding force of 120 ± 39 pN (mean±S.D, n = 34); their frequency of occurrence is 0.57, 0.65, 0.94, 0.98, 0.98, 1.00, 0.91, 1.00, respectively.
	Figure 4-Clusters obtained from the SMFS experiment in the native rod OS plasma membrane and disc membrane at an Lc value lower than 200 nm. (a) Superposition of 40 F-D curves for Cluster 1 from rod OS plasma membrane; the continuous lines represent the fitting of WLC model to each force peak, where the red line represents the WLC fit to the final force peak, providing the complete length of the protein pulled by the AFM stylus; the a.a. number of residues corresponds to the last force peak position. The percentage represents the probability of occurrence (filtering procedure provided n = 311). (b–f) Superposition of F-D curves as in panel a but for the other Clusters; the percentage represents the probability of occurrence; filtering procedure provided n = 121, n = 68, n = 19, n = 16, n = 19, respectively. (g) Superposition of 92 F-D curves for Cluster 1 from rod OS disc membrane; the continuous lines represent the fitting of WLC model to each force peak, where the red line represents the WLC fit to the final force peak providing the complete length of the protein pulled by the AFM stylus; the a.a. number of residues corresponds to the last force peak position. The percentage represents the probability of occurrence (filtering procedure provided n = 249). (h,i) Superposition of 87 and 57 F-D curves, respectively, as in panel g but for the other Clusters.
	Figure 5-Unfolding pathways of native rhodopsin. (a) Superposition of 55 F-D curves obtained from the unfolding of a single rhodopsin from single layered open disc membranes (unfolding from N-terminal): six force peaks. The first force peak at Lc values of 36 ± 8 a.a. (n = 19), 56 ± 5 a.a. (n = 38), 109 ± 9 a.a. (n = 55), 152 ± 6 a.a. (n = 49), 210 ± 4 a.a. (n = 55), and 245 ± 10 a.a. (n = 40), with a probability of 0.34, 0.68, 1.00, 0.88,1.00 and 0.74, respectively, and the unfolding force of 130 ± 19 pN, 90 ± 26 pN, 80 ± 19 pN, 85 ± 22 pN, 62 ± 31 pN, and 65 ± 19 pN, respectively. Fit with the WLC model reveals the number of a.a. corresponding to force peak positions. (b) Superposition of 87 F-D curves as in panel a but from double layered intact disc membranes (unfolding from C-terminal) with five force peaks at Lc values of 31 ± 6 a.a. (n = 66), 50 ± 5 a.a. (n = 58), 112 ± 8 a.a. (n = 87), 175 ± 10 a.a. (n = 87), and 240 ± 8 a.a. (n = 87), with a probability of 0.75, 0.66, 1.00, 1.00, and 1.00, respectively. Force peaks are, respectively, 127 ± 19 pN, 98 ± 18 pN, 86 ± 15 pN, 55 ± 10 pN, and 57 ± 20 pN. (c) Superposition of 121 F-D curves obtained from the unfolding of a single rhodopsin from the cytoplasmic side (C-terminal) of the rod OS plasma membranes with seven force peaks at Lc values at 31 ± 6 a.a. (n = 121), 67 ± 4 a.a. (n = 95), 97 ± 4 a.a. (n = 108), 115 ± 8 a.a. (n = 78), 154 ± 8 a.a. (n = 121), 185 ± 10 a.a. (n = 121), and 238 ± 6 a.a. (n = 102), with probabilities of 1.00, 0.78, 0.89, 0.64, 1.00, 1.00, and 0.84 respectively. The unfolding forces are respectively: 118 ± 45 pN, 145 ± 30 pN, 145 ± 25 pN, 95 ± 20 pN, 150 ± 10 pN, 155 ± 15 pN, and 125 ± 30 pN. (d–f) Histogram of Lc values (in nm) of force peaks obtained from all curves in panel (a–c), respectively, (bin 0.8 nm or ~2 a.a.); numbers represent the Lc in a.a. and the frequency of occurrence for every peak. (g–i) Cartoon representation of the secondary structure of rhodopsin mapped with a structurally stable segment obtained with SMFS in panels a–c or in panels d–f respectively. Yellow circles represent native cysteins that are responsible for the structural stability of bovine rhodopsin. Red circles and corresponding numbers (in a.a.) represent the force peak positions of rhodopsin molecule unfolded from those three different situations.
	Figure 6-Simulation of unfolding pathways of rhodopsin and hydrophobicity of the membrane effects. (a,c,e,g) Simulated force-distance traces for bovine rhodopsin (PDB code 1U19) pulled by the C-terminal at kBT = 0.52 ε for different values of the parameter εMEMBR as indicated ((a) 4.03 ε, (c) 5.64 ε, (e) 7.25 ε, (f) 10 ε). Each plot represents the superposition of 10 traces obtained from 10 independent simulations. (b,d,f,h) cartoon representations of the order in which the transmembrane helices unfold in the simulations of the left panels, as derived by a visual inspection of the trajectories. The colour map is the same as for the traces. The numbers on top of each peak correspond to the length of the stretch that is unfolded up to the time step when the force drops (expressed in number of amino acids, n, see SI 4 for details). (i) The angle α between the transmembrane helices D and E. Panels j,k, and l show results theoretically derived from atomistic MD simulation of rhodopsin in DPPC bilayer without cholesterol. (j) Probability distribution of the angle α in a membrane without cholesterol (red line) and with 50% cholesterol concentration (blue dotted line); (k) Hydrophobic (AHPHOB), and hydrophilic (AHPHIL) transmembrane SASA of rhodopsin as a function of the angle α; (l) Change in the relative population of metarhodopsin II and rhodopsin 𝑃𝑀𝐸𝑇𝐴𝑅𝐻𝑂𝐷(𝑐)𝑃𝑅𝐻𝑂𝐷(𝑐)/𝑃𝑀𝐸𝑇𝐴𝑅𝐻𝑂𝐷(0)𝑃𝑅𝐻𝑂𝐷(0) P M E T A R H O D ( c ) P R H O D ( c ) / P M E T A R H O D ( 0 ) P R H O D ( 0 ) as a function of the cholesterol concentration c in the lipid bilayer.
	Supplementary Figure 1: Sample preparation. a: Example of an IR light image of an intact rod cell from Xenopus laevis frog. b: representative AFM scanning image of the cytoplasmic site of rod cell plasma membrane after absorption on mica surface in the presence of recording solution. c: AFM topography of a native rod OS plasma membrane patch. d: enlargement of the AFM image of plasma membrane patch underlined in the black box in panel c. e: AFM topography of an open, spread-flattened native disc; four different surface types are evident: the centre of the disc with a height profile around 6 nm with densely packed rhodopsin (1); the disc rim region (2); co-isolated lipid surface without any protein (3) and mica surface (4). f: AFM topography of an intact rod OS disc membrane; three different surface types are evident: the centre of the disc with a height profile around 14 nm with densely packed rhodopsin (1); co-isolated lipid surface without any protein (2) and mica surface (3). g-h: height profile taken along the blue rod OS section in panel c and d respectively; the height of the plasma membrane was around 8±1.8 nm (n=22). i-j: height profile taken along the blue rod OS section; discs with one or two lipid bilayers had a height of 6.5±1.8 (n=25) and 14±1.7 nm (n=18) in panel e and f, respectively.
	Supplementary Figure 2: Procedure for the determination of the probability of force peaks from the Lc histogram: Step one provided the superposition of all the F-D curves obtained from the clusterization. a: example of a superposition of 67 F-D curves from CNGA1 unfolding, continuous line provided a representative WLC fittings to each force peak. Step two is solving the WLC equation for each curve at each point provided the global Lc histogram. b: global Lc histogram obtained from solving the WLC equation for each point of all the 67 F-D curves from panel a. Step three is to obtain the Lc maximum histogram, and fitting with Gaussian function for each distribution in Lc histogram provided the probability for each force peak. c: representation of a Lc maximum histogram obtained from panel b, the continuous lines represent the Gaussian fitting for individual distribution in Lc histogram.
	Supplementary Figure 3. Unfolding of rhodopsin from the OS plasma membrane treated with cyclodextrin. a: superposition of 4 F-D curves for Cluster 1 after the application of 1 mM cyclodexstrin (here named CD) for 3 minutes; the continuous lines represent the fitting of WLC model to each force peak. The percentage represents the probability of occurrence. b: as in panel a but with superposition of 4 F-D curves for Cluster 2. c: Plots representing the frequency versus the number of unfolding steps of rhodopsin in the different membranes with and without cyclodextrin.
	Supplementary Figure 4. a, b: correlation between the experimental values of n, the number of unfolded amino acids, as deduced by the values of Lc and the theoretical values of n, obtained as described in figure 6 (main text). The panel a corresponds to the simulation with εMEMBR=7.25ε, panel g (fig.6), compared with the experimental values for the plasma membrane (Fig. 4b). The panel b corresponds to the simulation with εMEMBR=10ε, panel e (fig. 6), compared with the experimental values for the discs (Fig. 4c). The colour map is the same as the one used in the top panels. The points with the same colouring (two blue points in panel a and two red points in panel b) correspond to ambiguous cases, in which, for instance, a single experimental peak may be associated with two theoretical peaks (and vice versa).
	Supplementary Figure 5. Plot of energy as a function of AHPHOB at different thickness of lipid intermediates. In a typical lipid bilayer the intermediate region connecting the fully hydrated polar headgroups to the fully dehydrated hydrophobic tails has a thickness of approximately 3 Å [1]. This is the rationale behind the choice of this parameter in the VMEMBR formula . However, we also verified that the exact choice of this parameter does not affect the qualitative behaviour of VMEMBR. We performed the same set of 4 MD simulations described above for cutoff 1 and 5 Å. In the figure, we show that the trend of the average energy as a function of the hydrophobic area remains qualitatively similar even if the thickness parameter is changed rather dramatically.
	Figure 1. AFM image of membrane patches from the rod OS disc and the plasma membrane (a) AFM topography from rod OS disc membrane showing the organization of rhodopsin in the single layered disc membrane. (b) AFM topography from rod OS plasma membrane. (c,d) Clusterization of the images in panel a and b according to their height ranges from 1–2.9 nm (area with red color) and 3–7 nm (area with green color), respectively. (e) Superposition of histograms of height profile from all the detected particles as in panel c from the images taken from rod OS disc membrane in different experiments, with a mean protrusion of 1.5 ± 0.4 nm (n = 18). (f) Superposition of histograms of height profile from all the detected particles as in panel d, from the images taken from rod OS plasma membrane in different experiments, with two different protrusions: height profile of 1.5 ± 0.7 nm and 4.9 ± 0.9 (n = 22).
	Figure 2. Identification of the spatial organization of CNG channels in the rod OS plasma membrane. (a) Selected membrane patch from the base of rod OS showing different topographical features. Acquisition of images at different times demonstrates stable (blue arrows) and unstable (green arrows) features. (b) High resolution image with protrusions from the lipid bilayer with different height; 1,2,3 are CNG channels while 4,5 are rhodopsin. (c) F-D curves obtained after pulling of selected protrusion (see numbered circles). (d) Superimposition of histograms of normalized counts/bin against Lc from 29 F-D curves (in red) of CNGA1 subunit from rod OS plasma membrane, and 157 F-D curves (in grey) of CNGA1 from oocyte plasma membrane.
	Figure 3. Single molecule unfolding of CNGA1 subunit in the closed and open states. (a) Superposition of 157 F-D curves (black lines) from oocyte plasma membrane overexpressing CNGA1 channels (modified from ref.7) and a single F-D curve of CNGA1 subunit (red trace) from rod OS plasma membrane, both in the absence of cGMP (closed state). (b) Representative F-D curves of CNGA1 subunit from rod OS plasma membrane; curves 1 and 2 are full length unfolding of CNGA1single subunit with an Lc value around 272 nm, while curves 3 and 4 are unfolding of a single CNGA1 subunit pulled up to S1 transmembrane domain with an Lc value around 231 nm. (c) Superposition of 36 F-D curves of CNGA1 subunit from rod OS plasma membrane in the absence of cGMP (closed state); continuous black lines are obtained from the fitting with WLC model and numbers indicate the corresponding values of Lc. (d) The same as in c but in the presence of 2 mM cGMP (open state). (e) Histogram of normalized counts/bin against Lc obtained from all the traces in panel c (bin-3 nm); numbers represent the corresponding Lc (mean±S.D, n = 36) values in nm and the relative probability (P): five force peaks with values of Lc equal to 114 ± 4, 153 ± 3, 186 ± 4, 229 ± 6, and 273 ± 5 nm; the frequency of occurrence is 0.98, 0.98, 1, 1.00, and 0.21, respectively, with an unfolding force of 95 ± 45 pN; number in red represents the characteristic peaks for CNGA1 channels in the closed state. In roman numerals the numbers of force peaks. (f) The same as in e but for all the traces in panel d; numbers in blue represent the characteristic peaks for CNGA1 channels in the open state: eight force peaks with Lc of 48 ± 2, 84 ± 2, 113 ± 3, 140 ± 3, 172 ± 3, 191 ± 5, 234 ± 4, and 276 ± 6 nm (n = 34), and higher unfolding force of 120 ± 39 pN (mean±S.D, n = 34); their frequency of occurrence is 0.57, 0.65, 0.94, 0.98, 0.98, 1.00, 0.91, 1.00, respectively.
	Figure 4. Clusters obtained from the SMFS experiment in the native rod OS plasma membrane and disc membrane at an Lc value lower than 200 nm. (a) Superposition of 40 F-D curves for Cluster 1 from rod OS plasma membrane; the continuous lines represent the fitting of WLC model to each force peak, where the red line represents the WLC fit to the final force peak, providing the complete length of the protein pulled by the AFM stylus; the a.a. number of residues corresponds to the last force peak position. The percentage represents the probability of occurrence (filtering procedure provided n = 311). (b–f) Superposition of F-D curves as in panel a but for the other Clusters; the percentage represents the probability of occurrence; filtering procedure provided n = 121, n = 68, n = 19, n = 16, n = 19, respectively. (g) Superposition of 92 F-D curves for Cluster 1 from rod OS disc membrane; the continuous lines represent the fitting of WLC model to each force peak, where the red line represents the WLC fit to the final force peak providing the complete length of the protein pulled by the AFM stylus; the a.a. number of residues corresponds to the last force peak position. The percentage represents the probability of occurrence (filtering procedure provided n = 249). (h,i) Superposition of 87 and 57 F-D curves, respectively, as in panel g but for the other Clusters.
	Figure 5. Unfolding pathways of native rhodopsin. (a) Superposition of 55 F-D curves obtained from the unfolding of a single rhodopsin from single layered open disc membranes (unfolding from N-terminal): six force peaks. The first force peak at Lc values of 36 ± 8 a.a. (n = 19), 56 ± 5 a.a. (n = 38), 109 ± 9 a.a. (n = 55), 152 ± 6 a.a. (n = 49), 210 ± 4 a.a. (n = 55), and 245 ± 10 a.a. (n = 40), with a probability of 0.34, 0.68, 1.00, 0.88,1.00 and 0.74, respectively, and the unfolding force of 130 ± 19 pN, 90 ± 26 pN, 80 ± 19 pN, 85 ± 22 pN, 62 ± 31 pN, and 65 ± 19 pN, respectively. Fit with the WLC model reveals the number of a.a. corresponding to force peak positions. (b) Superposition of 87 F-D curves as in panel a but from double layered intact disc membranes (unfolding from C-terminal) with five force peaks at Lc values of 31 ± 6 a.a. (n = 66), 50 ± 5 a.a. (n = 58), 112 ± 8 a.a. (n = 87), 175 ± 10 a.a. (n = 87), and 240 ± 8 a.a. (n = 87), with a probability of 0.75, 0.66, 1.00, 1.00, and 1.00, respectively. Force peaks are, respectively, 127 ± 19 pN, 98 ± 18 pN, 86 ± 15 pN, 55 ± 10 pN, and 57 ± 20 pN. (c) Superposition of 121 F-D curves obtained from the unfolding of a single rhodopsin from the cytoplasmic side (C-terminal) of the rod OS plasma membranes with seven force peaks at Lc values at 31 ± 6 a.a. (n = 121), 67 ± 4 a.a. (n = 95), 97 ± 4 a.a. (n = 108), 115 ± 8 a.a. (n = 78), 154 ± 8 a.a. (n = 121), 185 ± 10 a.a. (n = 121), and 238 ± 6 a.a. (n = 102), with probabilities of 1.00, 0.78, 0.89, 0.64, 1.00, 1.00, and 0.84 respectively. The unfolding forces are respectively: 118 ± 45 pN, 145 ± 30 pN, 145 ± 25 pN, 95 ± 20 pN, 150 ± 10 pN, 155 ± 15 pN, and 125 ± 30 pN. (d–f) Histogram of Lc values (in nm) of force peaks obtained from all curves in panel (a–c), respectively, (bin 0.8 nm or ~2 a.a.); numbers represent the Lc in a.a. and the frequency of occurrence for every peak. (g–i) Cartoon representation of the secondary structure of rhodopsin mapped with a structurally stable segment obtained with SMFS in panels a–c or in panels d–f respectively. Yellow circles represent native cysteins that are responsible for the structural stability of bovine rhodopsin. Red circles and corresponding numbers (in a.a.) represent the force peak positions of rhodopsin molecule unfolded from those three different situations.
	Figure 6. Simulation of unfolding pathways of rhodopsin and hydrophobicity of the membrane effects. (a,c,e,g) Simulated force-distance traces for bovine rhodopsin (PDB code 1U19) pulled by the C-terminal at kBT = 0.52 ε for different values of the parameter εMEMBR as indicated ((a) 4.03 ε, (c) 5.64 ε, (e) 7.25 ε, (f) 10 ε). Each plot represents the superposition of 10 traces obtained from 10 independent simulations. (b,d,f,h) cartoon representations of the order in which the transmembrane helices unfold in the simulations of the left panels, as derived by a visual inspection of the trajectories. The colour map is the same as for the traces. The numbers on top of each peak correspond to the length of the stretch that is unfolded up to the time step when the force drops (expressed in number of amino acids, n, see SI 4 for details). (i) The angle α between the transmembrane helices D and E. Panels j,k, and l show results theoretically derived from atomistic MD simulation of rhodopsin in DPPC bilayer without cholesterol. (j) Probability distribution of the angle α in a membrane without cholesterol (red line) and with 50% cholesterol concentration (blue dotted line); (k) Hydrophobic (AHPHOB), and hydrophilic (AHPHIL) transmembrane SASA of rhodopsin as a function of the angle α; (l) Change in the relative population of metarhodopsin II and rhodopsin \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\frac{{P}^{METARHOD}(c)}{{P}^{RHOD}(c)}/\frac{{P}^{METARHOD}(0)}{{P}^{RHOD}(0)}$$\end{document}PMETARHOD(c)PRHOD(c)/PMETARHOD(0)PRHOD(0) as a function of the cholesterol concentration c in the lipid bilayer.

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