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Mechanical and Chemical Unfolding of a Single Protein: a Comparison Proc. Natl. Acad. Sci. USA Vol. 96, pp. 3694–3699, March 1999 Biophysics Mechanical and chemical unfolding of a single protein: A comparison MARIANO CARRION-VAZQUEZ*, ANDRES F. OBERHAUSER*, SUSAN B. FOWLER†,PIOTR E. MARSZALEK*, SHELDON E. BROEDEL§,JANE CLARKE†, AND JULIO M. FERNANDEZ*¶ *Department of Physiology and Biophysics, Mayo Foundation, Rochester, MN 55905; §Athena Environmental Sciences, Inc., Baltimore, MD 21227; and †Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom Edited by Alan Fersht, University of Cambridge, Cambridge, United Kingdom, and approved January 28, 1999 (received for review November 23, 1998) ABSTRACT Is the mechanical unraveling of protein do- stability measured have been ‘‘in the range’’ of the results mains by atomic force microscopy (AFM) just a technological observed for isolated domains of this kind. However, the com- feat or a true measurement of their unfolding? By engineering parison between mechanical and chemical data has remained a protein made of tandem repeats of identical Ig modules, we uncertain because the range of unfolding and refolding rates of were able to get explicit AFM data on the unfolding rate of a these modules varies by 2 orders of magnitude, and the stability single protein domain that can be accurately extrapolated to ranges from 2 to 10 kcalymol (1 cal 5 4.18 J) (3–5, 13). zero force. We compare this with chemical unfolding rates for In this work, we use protein engineering to construct tandem untethered modules extrapolated to 0 M denaturant. The repeats of a single protein module and stretch it with AFM to unfolding rates obtained by the two methods are the same. examine its stability and folding kinetics. Tandem repeats are Furthermore, the transition state for unfolding appears at the necessary because the mechanical properties of a single module same position on the folding pathway when assessed by either cannot be directly studied by using AFM techniques. A single method. These results indicate that mechanical unfolding of a module will extend only for a short distance and fall into a region single protein by AFM does indeed reflect the same event that where we always observe a large amount of nonspecific interac- is observed in traditional unfolding experiments. The way is tions between the AFM tip and the substrate (,30 nm). In now open for the extensive use of AFM to measure folding contrast, tandem repeats of many modules extend well over the reactions at the single-molecule level. Single-molecule AFM region of nonspecific interactions and generate periodical pat- recordings have the added advantage that they define the terns that amplify the features of the individual modules and allow reaction coordinate and expose rare unfolding events that for a high signal-to-noise ratio. We have constructed recombinant cannot be observed in the absence of chemical denaturants. proteins composed of direct tandem repeats of Ig module 27 of the I band of human cardiac titin (I27). I27 (89 aa) was chosen Individually folded domains are common building blocks of because its structure has been determined by using NMR (14), proteins (1, 2). The native state of proteins is the most stable, and and it has a known stability (13). Furthermore, recent steered therefore, proteins rarely unfold spontaneously. For example, the molecular dynamics simulations modeled the extension of I27 unfolding of isolated Ig and fibronectin type III domains is a rare under an applied force (15). Through the use of a series of AFM event estimated to occur at a rate of 1023 to 1024 s21, whereas extension protocols, we reconstructed the folding pathway of refolding is typically much faster, at rates of '1to100s21 (3–6). tethered I27s. We compare the AFM results with those obtained Hence, unfolding is typically studied by using chemical denatur- on isolated, untethered modules by using standard chemical ation, which forces the domains into various degrees of unfolding. denaturation techniques. Our results demonstrate that the un- By using protein engineering combined with a variety of spec- folding rates obtained by the two methods are identical. Further- troscopic techniques such as NMR and fluorescence, it is possible more, we find that the transition state for unfolding appears at the to examine the folding of protein domains after chemical dena- same position on the folding trajectory obtained by using AFM turation (3, 7–9). These experimental approaches are widely used and chemical denaturants. These results are surprising and indi- and give information about the folding free energy, transition cate that mechanical unfolding of a single protein by AFM does state, and folding landscape. indeed reflect the same event that is observed in traditional The atomic force microscope (AFM) is a simple instrument unfolding experiments. Hence, our results open the way for the capable of causing the unfolding of a single protein by controlling extensive use of AFM as a tool for the measurement of protein- its length with Å-scale resolution (10, 11). AFM techniques folding reactions. trigger unfolding by applying force to a single protein, which MATERIALS AND METHODS increases the rate of unfolding exponentially, thus making it easily observable without requiring chemical denaturants (10–12). Construction of Poly(I27) Proteins. Two different recom- However, despite these developments, single protein recordings binant methods were used to synthesize and express direct by using AFM have remained limited, because when stretching tandem repeats of I27 monomers, with identical results. The the whole or part of a multimodular protein, it has been impos- first method is a multiple-step cloning technique based on a sible to assign experimental observables to individual domains previously described strategy (16). First, the I27 domain monomer unit was subcloned after PCR amplification of a because of their heterogeneity. Furthermore, it is not known 9 whether mechanical unraveling events represent true unfolding human cardiac muscle cDNA clone (10). The 5 primer events. This has been a point that investigators have tried to contained a BamHI restriction site that permitted in-frame cloning of the monomer into the expression vector pQE30 address in previous papers (10, 11). However, it has been possible 9 only to say that the unfolding and refolding rates observed and the (Qiagen, Chatsworth, CA). The 3 primer contained a BglII The publication costs of this article were defrayed in part by page charge This paper was submitted directly (Track II) to the Proceedings office. Abbreviations: AFM, atomic force microscope/microscopy; I27, hu- payment. This article must therefore be hereby marked ‘‘advertisement’’ in man cardiac titin I band module 27; GdmCl, guanidium chloride; accordance with 18 U.S.C. §1734 solely to indicate this fact. WLC, worm-like chain model. PNAS is available online at www.pnas.org. ¶To whom reprint requests should be addressed. 3694 Downloaded by guest on September 25, 2021 Biophysics: Carrion-Vazquez et al. Proc. Natl. Acad. Sci. USA 96 (1999) 3695 restriction site, two Cys codons located 39 to the BglII site and all-trans in the folded state. It is probable that the slower in-frame with the I27 domain, and two in-frame stop codons. phases, which show little denaturant dependence, are phases The PCR product was cloned into pUC19 linearized with reflecting the refolding of proteins limited by proline isomer- BamHI and SmaI. The 8-domain synthetic gene was then ization, as has been observed in other proteins, including those constructed by iterative cloning of monomer into monomer, with a similar Ig-like fold. Folding in the absence of denaturant dimer into dimer, and tetramer into tetramer. The final was performed by applying a pH shift, from pH 12.4 to pH 7.4. construct contained eight direct repeats of the I27 domain, an Unfolding was slow, and data were collected for more than amino-terminal His tag for purification, and two carboxyl- 2,000 sec. In this case, unfolding was monitored by loss of terminal Cys codons used for covalent attachment to the fluorescence at 320 nm (excitation 280 nm) after manual RS gold-covered coverslips. The full-length construct, I27 8, mixing in a 1-cm-pathlength cuvette. The data fit well to a results in the following amino acid additions: (i) the amino- single exponential term plus a term to account for baseline terminal sequence is Met-Arg-Gly-Ser-(His)6-Gly-Ser-I27 drift caused by photolysis. A chevron plot of the data (Fig. 6A) codons; (ii) the junction between the domains (BamHI-BglII shows the unfolding and folding dependencies on denaturant hybrid site) is Arg-Ser; and (iii) the protein terminates in concentration. The data were fit with a simple two-state kinetic RS Cys-Cys. The synthetic I27 8 was cloned in an Escherichia coli model (Fig. 6A, solid line) given by recombination-defective strain, Sure-2 (Stratagene), ex- 21 5 @ H2O ~ @ #! 1 H2O ~ pressed in the M15 strain, and purified by Ni -affinity chro- ln kobs ln kf exp mkf D ku exp mku[D])], matography under nondenaturing conditions. Elution from the H2O5 21 H2O 5 3 24 21 52 21 resin was with 100 mM imidazole (pH 6.0). In a second where kf 190 s , ku 4.9 10 s , mkf 3.9 M ; 5 21 strategy, directional DNA concatemerization was done by and mku 0.26 M . self-ligation of the sticky ends of the nonpalindromic CTCGGG AvaI restriction site (17, 18). I27 cDNA with flanking AvaI sites was isolated by using PCR. After self- RESULTS AND DISCUSSION ligation, the concatemers were cloned into a custom-made Engineering an I27 Polyprotein.We used recombinant DNA GLG expression vector. I27 12 was expressed in the recombina- 1 techniques to construct direct tandem repeats of a single Ig tion-defective strain BLR(DE3) (Novagene), purified by Ni2 - domain from titin (see Materials and Methods).
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