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10358.Full.Pdf Bridging the gaps in design methodologies by evolutionary optimization of the stability and proficiency of designed Kemp eliminase KE59 Olga Khersonskya,1, Gert Kissb,2, Daniela Röthlisbergerc,3, Orly Dymd, Shira Albeckd, Kendall N. Houkb, David Bakerc,e,f, and Dan S. Tawfika,4 aDepartment of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel; bDepartment of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095; cDepartment of Biochemistry, University of Washington, Seattle, WA 98195; dIsrael Structural Proteomics Center, Weizmann Institute of Science, Rehovot 76100, Israel; eBiomolecular Structure and Design, University of Washington, Seattle, WA 98195; and fHoward Hughes Medical Institute, University of Washington, Seattle, WA 98195 Edited by William F. DeGrado, UCSF School of Pharmacy, San Francisco, CA, and approved May 4, 2012 (received for review December 26, 2011) Computational design is a test of our understanding of enzyme cat- ciple, directed evolution—protein optimization by cycles of alysis and a means of engineering novel, tailor-made enzymes. random mutagenesis and selection—could be applied to optimize While the de novo computational design of catalytically efficient computationally designed enzymes. However, can directed evolu- enzymes remains a challenge, designed enzymes may comprise tion bridge the orders-of-magnitude gap between computational unique starting points for further optimization by directed evolu- design and enzyme-like catalytic efficiencies? tion. Directed evolution of two computationally designed Kemp We have previously generated a series of computationally de- eliminases, KE07 and KE70, led to low to moderately efficient en- signed Kemp eliminases (12). These were designed to have apolar k ∕K ≤ × 4 −1 −1 zymes ( cat m values of 5 10 M s ). Here we describe the active sites and a base (carboxylate or histidine) aligned against optimization of a third design, KE59. Although KE59 was the the C-H bond. The relative locations of the catalytic groups most catalytically efficient Kemp eliminase from this design series around the reaction’s TS were optimized by quantum mechanical k ∕K (by cat m, and by catalyzing the elimination of nonactivated calculations. Apart from the catalytic base, additional residues benzisoxazoles), its impaired stability prevented its evolutionary were included: aromatic residue(s) to promote substrate binding optimization. To boost KE59’s evolvability, stabilizing consensus and delocalize the TS’s negative charge, and hydrogen donors for mutations were included in the libraries throughout the directed the stabilization of the phenolate’s negative charge. The designed evolution process. The libraries were also screened with less Kemp eliminases were obtained by identifying protein scaffolds in activated substrates. Sixteen rounds of mutation and selection which the designed active site configurations could be realized led to >2,000-fold increase in catalytic efficiency, mainly via higher using the RosettaMatch algorithm (14) and then optimizing k k ∕K cat values. The best KE59 variants exhibited cat m values up to TS binding with RosettaDesign (12). The active designs exhibited × 6 −1 −1 k ∕k ≤ 7 ∕ ≤10 −1 −1 0.6 10 M s , and cat uncat values of 10 almost regardless kcat Km values in the range of M s (KE07) up to of substrate reactivity. Biochemical, structural, and molecular 160 M−1s−1 (KE59)—orders of magnitude lower than the cata- ∕ dynamics (MD) simulation studies provided insights regarding lytic efficiency exhibited by natural enzymes [kcat Km values of the optimization of KE59. Overall, the directed evolution of three 104–108 M−1s−1 (15)]. different designed Kemp eliminases, KE07, KE70, and KE59, de- The KE07 design was optimized by directed evolution (16), monstrates that computational designs are highly evolvable and and KE70 by a combination of directed evolution and computa- ∕ can be optimized to high catalytic efficiencies. tional design (17). The kcat Km values of optimized KE07 and KE70 variants (2.4 × 103–5 × 104 M−1s−1) compare well with computational protein design ∣ enzyme mimic other enzyme mimics but are still inferior to natural enzymes. Further, these Kemp eliminases catalyze only the elimination of he endeavor of making enzyme-like catalysts spans several the activated 5-nitro-benzisoxazole substrate (5-nitro BI). Here Tdecades (1) with the Kemp elimination being a thoroughly we describe the optimization of KE59. This design was based explored model (2–7). In this activated model system, base- on the a∕β barrel scaffold of indole-3-glycerolphophate synthase catalyzed proton elimination from carbon is concerted with the [IGPS, Protein Data Bank (PDB) entry 1A53]. The designed cleavage of nitrogen-oxygen bond, thus leading to the cyanophe- active site comprised a tightly packed hydrophobic pocket that nol product (Fig. 1A). Activation of a carboxylate base catalyst envelops the nonpolar substrate (Fig. 1B). The designed E230 by desolvation is efficiently mimicked by aprotic dipolar solvents acts as the catalytic base, and W109 was introduced to facilitate such as acetonitrile and by various enzyme mimics. Effective alignment of the substrate and charge-dispersing interactions that Author contributions: O.K., K.N.H., D.B., and D.S.T. designed research; O.K., G.K., and D.R. stabilize the negatively charged transition state (TS) have also performed research; O.K., G.K., O.D., S.A., D.B., and D.S.T. analyzed data; and O.K., G.K., been achieved by various enzyme mimics that catalyze the Kemp O.D., D.B., and D.S.T. wrote the paper. elimination (8, 9). However, generation of a (wo)manmade active The authors declare no conflict of interest. site that exhibits all these features and performs as well as natural This article is a PNAS Direct Submission. enzymes, remains a challenge. Data deposition: Crystallography, atomic coordinates, and structure factors have been Computational methods for predicting structure from sequence deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 3UXA, 3UXD, 3UY8, at atomic accuracy provide a new approach to enzyme engineering 3UYC, 3UZ5, and 3UZJ). (10–12). The design involves two steps: (i) designing an active-site 1Present address: Department of Biochemistry, University of Washington, Seattle, configuration that may confer efficient catalysis, (ii) computing a WA 98195. sequence that confers the desired configuration. Both steps are 2Present address: Department of Chemistry, Stanford University, Stanford, CA 94305. currently far from optimal, as the catalytic efficiency of designed 3Present address: Arzeda Corp., Seattle, WA 98102. enzymes falls far behind that of natural enzymes. Further, as with 4To whom correspondence should be addressed. E-mail: [email protected]. other enzyme mimics, computational designs tackle activated mod- This article contains supporting information online at www.pnas.org/lookup/suppl/ el systems and fail to catalyze challenging reactions (13). In prin- doi:10.1073/pnas.1121063109/-/DCSupplemental. 10358–10363 ∣ PNAS ∣ June 26, 2012 ∣ vol. 109 ∣ no. 26 www.pnas.org/cgi/doi/10.1073/pnas.1121063109 Downloaded by guest on September 28, 2021 A be mutated simultaneously, this could lead to protein destabiliza- tion, because many consensus mutations are deleterious (24). Therefore, the consensus mutations were spiked into the KE59 libraries, to allow various combinations of stabilizing mutations (26). The importance of combinatorial incorporation is high- lighted by the fact that consensus mutations at only 10 out of 23 positions were incorporated into the evolved KE59 variants. B The mutations were incorporated in the first two rounds of directed evolution of KE59, and the variants were screened S210 S179 for increased activity. Incorporation of 6–10 consensus mutations A208 I177 significantly improved the soluble expression of KE59 (from <2 mg protein∕L culture to >30 mg protein∕L culture; see SI V158 Appendix, Fig. S2), and enabled the accumulation of other muta- E230 tions that led to higher catalytic activity. The stabilizing mutations V50 A156 were located at the protein surface, either in the loops or helices, and they had little effect on the kinetic parameters of KE59 (Table 1). Following another two rounds of directed evolution, V80 W109 I132 there was a decrease in the expression of the evolved variants due to the destabilizing effect of function-modifying mutations G130 (19). Therefore, at Round 5, consensus mutations were included again and combinations that were not observed in the first stabi- lization attempt were incorporated. The incorporated mutations Fig. 1. The active site of the KE59 design. (A) Kemp elimination of 5-nitro- included mutations of solvent-exposed aromatic residues to smal- benzisoxazole. (B) The residues that were designed to create the Kemp elim- ler hydrophobic residues (W7A, F21L, Y75G, Y151L, F245L), inase active site (green), and the modeled 5-nitro BI (magenta). [Numbering mutations of solvent-exposed leucines to charged/polar residues of residues in this paper is n − 1 relative to the numbering in the previous (L14R/K and L247Q), and mutations resulting in opposite publication, due to omission of N-terminal M (12)]. SI Appendix A charges (K9E, E142K) (see , Fig. S3 ). BIOPHYSICS AND Due to the irreversibility of thermal denaturation of KE59 var- charge delocalization by π-stacking to the transition state. S179 COMPUTATIONAL BIOLOGY iants, the effect of the consensus mutations on KE59 stability and S210 were included to provide hydrogen-bonding interac- could be examined only by measuring the melting temperatures tions with the substrate’s nitro group. KE59’s long loops resulted (T ) of KE59 variants by residual activity (see SI Appendix, in a deep pocket, which may have made KE59 the most active M −1 −1 Fig. S4). These apparent T values did not correlate with soluble design within this series (k ∕K ≥ 160 M s ). M cat m expression levels (see SI Appendix, Fig. S2), possibly due to the As other KE designs, KE59 was designed to catalyze the elim- LG fact that many consensus mutations affect kinetic rather than ination of 5-nitro BI, an activated substrate with a pKa of 4.1.
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