Substrate Binding Induces Conformational Changes in a Class A β-lactamase That Prime It for Catalysis

Langan, Patricia S.; Vandavasi, Venu Gopal; Cooper, Sarah J.; Weiss, Kevin L.; Ginell, Stephan L.; Parks, Jerry M.; Coates, Leighton

doi:10.1021/acscatal.7b04114

Title: Substrate Binding Induces Conformational Changes in a Class A β-lactamase That Prime It for Catalysis

Journal Article · 15 February 2018 · ACS Catalysis

DOI: https://doi.org/10.1021/acscatal.7b04114 · OSTI ID:1459304

^[1];

^[2];

^[1]; Ginell, Stephan L. ^[3];

^[4];

^[1]

Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Univ. of Tennessee, Knoxville, TN (United States)
Argonne National Lab. (ANL), Argonne, IL (United States); Univ. at Buffalo, Buffalo, NY (United States)
Univ. of Tennessee, Knoxville, TN (United States); Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

Here, the emergence and dissemination of bacterial resistance to β-lactam antibiotics via β-lactamase enzymes is a serious problem in clinical settings, often leaving few treatment options for infections resulting from multidrug-resistant superbugs. Understanding the catalytic mechanism of β-lactamases is important for developing strategies to overcome resistance. Binding of a substrate in the active site of an enzyme can alter the conformations and pK_as of catalytic residues, thereby contributing to enzyme catalysis. Here we report X-ray and neutron crystal structures of the class A Toho-1 β-lactamase in the apo form and an X-ray structure of a Michaelis-like complex with the cephalosporin antibiotic cefotaxime in the active site. Comparison of these structures reveals that substrate binding induces a series of changes. The side chains of conserved residues important in catalysis, Lys73 and Tyr105, and the main chain of Ser130 alter their conformations, with Nζ of Lys73 moving closer to the position of the conserved catalytic nucleophile Ser70. This movement of Lys73 closer to Ser70 is consistent with proton transfer between the two residues prior to acylation. In combination with the tightly bound catalytic water molecule located between Glu166 and the position of Ser70, the enzyme is primed for catalysis when Ser70 is activated for nucleophilic attack of the β-lactam ring. Quantum mechanical/molecular mechanical (QM/MM) free energy simulations of models of the wild-type enzyme show that proton transfer from the Nζ of Lys73 to the Oε2 atom of Glu166 is more thermodynamically favorable than when it is absent. Taken together, our findings indicate that substrate binding enhances the favorability of the initial proton transfer steps that precede the formation of the acyl-enzyme intermediate.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); USDOE Office of Science (SC), Basic Energy Sciences (BES); National Science Foundation (NSF)

Grant/Contract Number:: AC05-00OR22725; AC02-06CH11357

OSTI ID:: 1459304

Alternate ID(s):: OSTI ID: 1485285

Journal Information:: ACS Catalysis, Vol. 8, Issue 3; ISSN 2155-5435

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

Citation Metrics:

Cited by: 21 works

Citation information provided by
Web of Science

References (79)

Penicillin as a Chemotherapeutic Agent Chain, E.; Florey, H. W.; Gardner, A. D. The Lancet, Vol. 236, Issue 6104 https://doi.org/10.1016/S0140-6736(01)08728-1	journal	August 1940
Foreword Richmond, S. M. H. Clinical Infectious Diseases, Vol. 10, Issue 4 https://doi.org/10.1093/clinids/10.4.677	journal	July 1988
A Brief History of the Antibiotic Era: Lessons Learned and Challenges for the Future Aminov, Rustam I. Frontiers in Microbiology, Vol. 1 https://doi.org/10.3389/fmicb.2010.00134	journal	January 2010
Extended-Spectrum -Lactamases in the 21st Century: Characterization, Epidemiology, and Detection of This Important Resistance Threat Bradford, P. A. Clinical Microbiology Reviews, Vol. 14, Issue 4 https://doi.org/10.1128/CMR.14.4.933-951.2001	journal	October 2001
Three Decades of -Lactamase Inhibitors Drawz, S. M.; Bonomo, R. A. Clinical Microbiology Reviews, Vol. 23, Issue 1 https://doi.org/10.1128/CMR.00037-09	journal	January 2010
Origins and Evolution of Antibiotic Resistance Davies, J.; Davies, D. Microbiology and Molecular Biology Reviews, Vol. 74, Issue 3 https://doi.org/10.1128/MMBR.00016-10	journal	August 2010
What's new in antibiotic resistance? Focus on beta-lactamases Babic, M.; Hujer, A.; Bonomo, R. Drug Resistance Updates, Vol. 9, Issue 3 https://doi.org/10.1016/j.drup.2006.05.005	journal	June 2006
A standard numbering scheme for the class A β-lactamases Ambler, R. P.; Coulson, A. F. W.; Frère, J. M. Biochemical Journal, Vol. 276, Issue 1 https://doi.org/10.1042/bj2760269	journal	May 1991
A functional classification scheme for beta-lactamases and its correlation with molecular structure Bush, K.; Jacoby, G. A.; Medeiros, A. A. Antimicrobial Agents and Chemotherapy, Vol. 39, Issue 6 https://doi.org/10.1128/AAC.39.6.1211	journal	June 1995
Metallo- -Lactamases: the Quiet before the Storm? Walsh, T. R.; Toleman, M. A.; Poirel, L. Clinical Microbiology Reviews, Vol. 18, Issue 2 https://doi.org/10.1128/CMR.18.2.306-325.2005	journal	April 2005
The β-lactamase cycle: a tale of selective pressure and bacterial ingenuity Matagne, André; Dubus, Alain; Galleni, Moreno Natural Product Reports, Vol. 16, Issue 1 https://doi.org/10.1039/a705983c	journal	January 1999
Growing Group of Extended-Spectrum -Lactamases: the CTX-M Enzymes Bonnet, R. Antimicrobial Agents and Chemotherapy, Vol. 48, Issue 1 https://doi.org/10.1128/AAC.48.1.1-14.2004	journal	December 2003
Extended-spectrum and inhibitor-resistant TEM-type beta-lactamases: mutations, specificity, and three-dimensional structure Knox, J. R. Antimicrobial Agents and Chemotherapy, Vol. 39, Issue 12 https://doi.org/10.1128/AAC.39.12.2593	journal	December 1995
Catalytic properties of class A β-lactamases: efficiency and diversity Matagne, André; Lamotte-Brasseur, Josette; FrÈRe, Jean-Marie Biochemical Journal, Vol. 330, Issue 2 https://doi.org/10.1042/bj3300581	journal	March 1998
CTX-M-type β-lactamases: an emerging group of extended-spectrum enzymes Tzouvelekis, L. S.; Tzelepi, E.; Tassios, P. T. International Journal of Antimicrobial Agents, Vol. 14, Issue 2 https://doi.org/10.1016/S0924-8579(99)00165-X	journal	March 2000
TEM- and SHV-derived extended-spectrum β-lactamases: relationship between selection, structure and function Bois, S. K. Du; Marriott, M. S.; Amyes, S. G. B. Journal of Antimicrobial Chemotherapy, Vol. 35, Issue 1 https://doi.org/10.1093/jac/35.1.7	journal	January 1995
Third-generation cephalosporin resistance among Gram-negative bacilli causing meningitis in neurosurgical patients: significant challenges in ensuring effective antibiotic therapy O'Neill, E.; Humphreys, H.; Phillips, J. Journal of Antimicrobial Chemotherapy, Vol. 57, Issue 2 https://doi.org/10.1093/jac/dki462	journal	December 2005
Crystal structure of the E166A mutant of extended-spectrum β-lactamase toho-1 at 1.8 Å resolution 1 1Edited by R. Huber Ibuka, Akiko; Taguchi, Ayako; Ishiguro, Masaji Journal of Molecular Biology, Vol. 285, Issue 5 https://doi.org/10.1006/jmbi.1998.2432	journal	February 1999
Crystal Structure of Extended-Spectrum β-Lactamase Toho-1: Insights into the Molecular Mechanism for Catalytic Reaction and Substrate Specificity Expansion ^† ^, ^‡ Ibuka, Akiko Shimizu; Ishii, Yoshikazu; Galleni, Moreno Biochemistry, Vol. 42, Issue 36 https://doi.org/10.1021/bi0342822	journal	September 2003
Acyl-intermediate Structures of the Extended-spectrum Class A β-Lactamase, Toho-1, in Complex with Cefotaxime, Cephalothin, and Benzylpenicillin Shimamura, Tatsuro; Ibuka, Akiko; Fushinobu, Shinya Journal of Biological Chemistry, Vol. 277, Issue 48 https://doi.org/10.1074/jbc.M207884200	journal	September 2002
Cloning and sequence of the gene encoding a cefotaxime-hydrolyzing class A beta-lactamase isolated from Escherichia coli Ishii, Y.; Ohno, A.; Taguchi, H. Antimicrobial Agents and Chemotherapy, Vol. 39, Issue 10 https://doi.org/10.1128/AAC.39.10.2269	journal	October 1995
Molecular structure of the acyl-enzyme intermediate in β-lactam hydrolysis at 1.7 Å resolution Strynadka, Natalie C. J.; Adachi, Hiroyuki; Jensen, Susan E. Nature, Vol. 359, Issue 6397 https://doi.org/10.1038/359700a0	journal	October 1992
An Ultrahigh Resolution Structure of TEM-1 β-Lactamase Suggests a Role for Glu166 as the General Base in Acylation Minasov, George; Wang, Xiaojun; Shoichet, Brian K. Journal of the American Chemical Society, Vol. 124, Issue 19 https://doi.org/10.1021/ja0259640	journal	May 2002
Ultrahigh Resolution Structure of a Class A β-Lactamase: On the Mechanism and Specificity of the Extended-spectrum SHV-2 Enzyme Nukaga, Michiyoshi; Mayama, Kayoko; Hujer, Andrea M. Journal of Molecular Biology, Vol. 328, Issue 1 https://doi.org/10.1016/S0022-2836(03)00210-9	journal	April 2003
Site-Directed Mutagenesis of Glutamate-166 in .beta.-Lactamase Leads to a Branched Path Mechanism Escobar, Walter A.; Tan, Anthony K.; Lewis, Evan R. Biochemistry, Vol. 33, Issue 24 https://doi.org/10.1021/bi00190a015	journal	June 1994
The Importance of a Critical Protonation State and the Fate of the Catalytic Steps in Class A β-Lactamases and Penicillin-binding Proteins Golemi-Kotra, Dasantila; Meroueh, Samy O.; Kim, Choonkeun Journal of Biological Chemistry, Vol. 279, Issue 33 https://doi.org/10.1074/jbc.M313143200	journal	May 2004
Lysine-73 Is Involved in the Acylation and Deacylation of β-Lactamase ^† Lietz, Eric J.; Truher, Heather; Kahn, Debra Biochemistry, Vol. 39, Issue 17 https://doi.org/10.1021/bi992681k	journal	May 2000
Site-directed Mutagenesis of Glutamate 166 in Two β-Lactamases: KINETIC AND MOLECULAR MODELING STUDIES Guillaume, Gilliane; Vanhove, Marc; Lamotte-Brasseur, Josette Journal of Biological Chemistry, Vol. 272, Issue 9 https://doi.org/10.1074/jbc.272.9.5438	journal	February 1997
Neutron and X-ray Crystal Structures of a Perdeuterated Enzyme Inhibitor Complex Reveal the Catalytic Proton Network of the Toho-1 β-Lactamase for the Acylation Reaction Tomanicek, Stephen J.; Standaert, Robert F.; Weiss, Kevin L. Journal of Biological Chemistry, Vol. 288, Issue 7 https://doi.org/10.1074/jbc.M112.436238	journal	December 2012
Exploring the Mechanism of β-Lactam Ring Protonation in the Class A β-lactamase Acylation Mechanism Using Neutron and X-ray Crystallography Vandavasi, Venu Gopal; Weiss, Kevin L.; Cooper, Jonathan B. Journal of Medicinal Chemistry, Vol. 59, Issue 1 https://doi.org/10.1021/acs.jmedchem.5b01215	journal	December 2015
Active-Site Protonation States in an Acyl-Enzyme Intermediate of a Class A β-Lactamase with a Monobactam Substrate Vandavasi, Venu Gopal; Langan, Patricia S.; Weiss, Kevin L. Antimicrobial Agents and Chemotherapy, Vol. 61, Issue 1 https://doi.org/10.1128/AAC.01636-16	journal	October 2016
Toward the Accurate Modeling of DNA: The Importance of Long-Range Electrostatics York, Darrin M.; Yang, Weitao; Lee, Hsing Journal of the American Chemical Society, Vol. 117, Issue 17 https://doi.org/10.1021/ja00122a034	journal	May 1995
Periodic Boundary Conditions in QM/MM Calculations: Implementation and Tests Vasilevskaya, Tatiana; Thiel, Walter Journal of Chemical Theory and Computation, Vol. 12, Issue 8 https://doi.org/10.1021/acs.jctc.6b00269	journal	July 2016
Combined Quantum Mechanics/Molecular Mechanics (QM/MM) Methods in Computational Enzymology van der Kamp, Marc W.; Mulholland, Adrian J. Biochemistry, Vol. 52, Issue 16 https://doi.org/10.1021/bi400215w	journal	April 2013
Identification of Glu166 as the General Base in the Acylation Reaction of Class A β-Lactamases through QM/MM Modeling Hermann, Johannes C.; Ridder, Lars; Mulholland, Adrian J. Journal of the American Chemical Society, Vol. 125, Issue 32 https://doi.org/10.1021/ja034434g	journal	August 2003
Mechanisms of Antibiotic Resistance: QM/MM Modeling of the Acylation Reaction of a Class A β-Lactamase with Benzylpenicillin Hermann, Johannes C.; Hensen, Christian; Ridder, Lars Journal of the American Chemical Society, Vol. 127, Issue 12 https://doi.org/10.1021/ja044210d	journal	March 2005
Ab Initio QM/MM Study of Class A β-Lactamase Acylation: Dual Participation of Glu166 and Lys73 in a Concerted Base Promotion of Ser70 Meroueh, Samy O.; Fisher, Jed F.; Schlegel, H. Bernhard Journal of the American Chemical Society, Vol. 127, Issue 44 https://doi.org/10.1021/ja051592u	journal	November 2005
High Level QM/MM Modeling of the Formation of the Tetrahedral Intermediate in the Acylation of Wild Type and K73A Mutant TEM-1 Class A β-Lactamase Hermann, Johannes C.; Pradon, Juliette; Harvey, Jeremy N. The Journal of Physical Chemistry A, Vol. 113, Issue 43 https://doi.org/10.1021/jp9037254	journal	September 2009
Molecular mechanisms of antibiotic resistance: QM/MM modelling of deacylation in a class A β-lactamase Hermann, Johannes C.; Ridder, Lars; Höltje, Hans-Dieter Org. Biomol. Chem., Vol. 4, Issue 2 https://doi.org/10.1039/B512969A	journal	January 2006
QM/MM simulations as an assay for carbapenemase activity in class A β-lactamases Chudyk, Ewa I.; Limb, Michael A. L.; Jones, Charlotte Chem. Commun., Vol. 50, Issue 94 https://doi.org/10.1039/C4CC06495J	journal	January 2014
Mechanisms of proton relay and product release by Class A β‐lactamase at ultrahigh resolution Lewandowski, Eric M.; Lethbridge, Kathryn G.; Sanishvili, Ruslan The FEBS Journal, Vol. 285, Issue 1 https://doi.org/10.1111/febs.14315	journal	November 2017
Ligand-Induced Proton Transfer and Low-Barrier Hydrogen Bond Revealed by X-ray Crystallography Nichols, Derek A.; Hargis, Jacqueline C.; Sanishvili, Ruslan Journal of the American Chemical Society, Vol. 137, Issue 25 https://doi.org/10.1021/jacs.5b00749	journal	June 2015
The structure of Toho1 β-lactamase in complex with penicillin reveals the role of Tyr105 in substrate recognition Langan, Patricia S.; Vandavasi, Venu Gopal; Weiss, Kevin L. FEBS Open Bio, Vol. 6, Issue 12 https://doi.org/10.1002/2211-5463.12132	journal	November 2016
The active site protonation states of perdeuterated Toho-1 β-lactamase determined by neutron diffraction support a role for Glu166 as the general base in acylation Tomanicek, Stephen J.; Wang, Kathy K.; Weiss, Kevin L. FEBS Letters, Vol. 585, Issue 2 https://doi.org/10.1016/j.febslet.2010.12.017	journal	December 2010
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	journal	January 2010
Overview of the CCP 4 suite and current developments Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444910045749	journal	March 2011
A short history of SHELX Sheldrick, George M. Acta Crystallographica Section A Foundations of Crystallography, Vol. 64, Issue 1, p. 112-122 https://doi.org/10.1107/S0108767307043930	journal	December 2007
The Macromolecular Neutron Diffractometer MaNDi at the Spallation Neutron Source Coates, Leighton; Cuneo, Matthew J.; Frost, Matthew J. Journal of Applied Crystallography, Vol. 48, Issue 4 https://doi.org/10.1107/S1600576715011243	journal	July 2015
The macromolecular neutron diffractometer (MaNDi) at the Spallation Neutron Source, Oak Ridge: enhanced optics design, high-resolution neutron detectors and simulated diffraction Coates, L.; Stoica, A. D.; Hoffmann, C. Journal of Applied Crystallography, Vol. 43, Issue 3 https://doi.org/10.1107/S0021889810008587	journal	April 2010
Protein structures by spallation neutron crystallography Langan, Paul; Fisher, Zoë; Kovalevsky, Andrii Journal of Synchrotron Radiation, Vol. 15, Issue 3 https://doi.org/10.1107/S0909049508000824	journal	April 2008
LSCALE – the new normalization, scaling and absorption correction program in the Daresbury Laue software suite Arzt, Steffi; Campbell, John W.; Harding, Marjorie M. Journal of Applied Crystallography, Vol. 32, Issue 3 https://doi.org/10.1107/S0021889898015350	journal	June 1999
LAUEGEN version 6.0 and INTLDM Campbell, J. W.; Hao, Q.; Harding, M. M. Journal of Applied Crystallography, Vol. 31, Issue 3 https://doi.org/10.1107/S0021889897016683	journal	June 1998
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
Improvement of crystal quality by surface mutations of β-lactamase Toho-1 Shimamura, Tatsuro; Nitanai, Yasushi; Uchiyama, Takuro Acta Crystallographica Section F Structural Biology and Crystallization Communications, Vol. 65, Issue 4 https://doi.org/10.1107/S1744309109008240	journal	March 2009
The catalytic efficiency (kcat/Km) of the class A β-lactamase Toho-1 correlates with the thermal stability of its catalytic intermediate analog Nitanai, Yasushi; Shimamura, Tatsuro; Uchiyama, Takuro Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Vol. 1804, Issue 4 https://doi.org/10.1016/j.bbapap.2009.10.023	journal	April 2010
The Catalytic Mechanism of an Aspartic Proteinase Explored with Neutron and X-ray Diffraction Coates, Leighton; Tuan, Han-Fang; Tomanicek, Stephen Journal of the American Chemical Society, Vol. 130, Issue 23 https://doi.org/10.1021/ja801269x	journal	June 2008
The determination of protonation states in proteins Ahmed, H. U.; Blakeley, M. P.; Cianci, M. Acta Crystallographica Section D Biological Crystallography, Vol. 63, Issue 8 https://doi.org/10.1107/S0907444907029976	journal	July 2007
MolProbity : all-atom structure validation for macromolecular crystallography Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1 https://doi.org/10.1107/S0907444909042073	journal	December 2009
Development and testing of a general amber force field Wang, Junmei; Wolf, Romain M.; Caldwell, James W. Journal of Computational Chemistry, Vol. 25, Issue 9 https://doi.org/10.1002/jcc.20035	journal	January 2004
Fast, efficient generation of high-quality atomic charges. AM1-BCC model: I. Method Jakalian, Araz; Bush, Bruce L.; Jack, David B. Journal of Computational Chemistry, Vol. 21, Issue 2 https://doi.org/10.1002/(SICI)1096-987X(20000130)21:2<132::AID-JCC5>3.0.CO;2-P	journal	January 2000
Fast, efficient generation of high-quality atomic charges. AM1-BCC model: II. Parameterization and validation Jakalian, Araz; Jack, David B.; Bayly, Christopher I. Journal of Computational Chemistry, Vol. 23, Issue 16 https://doi.org/10.1002/jcc.10128	journal	October 2002
The implementation of a fast and accurate QM/MM potential method in Amber Walker, Ross C.; Crowley, Michael F.; Case, David A. Journal of Computational Chemistry, Vol. 29, Issue 7 https://doi.org/10.1002/jcc.20857	journal	January 2008
ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB Maier, James A.; Martinez, Carmenza; Kasavajhala, Koushik Journal of Chemical Theory and Computation, Vol. 11, Issue 8 https://doi.org/10.1021/acs.jctc.5b00255	journal	July 2015
Comparison of simple potential functions for simulating liquid water Jorgensen, William L.; Chandrasekhar, Jayaraman; Madura, Jeffry D. The Journal of Chemical Physics, Vol. 79, Issue 2 https://doi.org/10.1063/1.445869	journal	July 1983
Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes Ryckaert, Jean-Paul; Ciccotti, Giovanni; Berendsen, Herman J. C. Journal of Computational Physics, Vol. 23, Issue 3 https://doi.org/10.1016/0021-9991(77)90098-5	journal	March 1977
Settle: An analytical version of the SHAKE and RATTLE algorithm for rigid water models Miyamoto, Shuichi; Kollman, Peter A. Journal of Computational Chemistry, Vol. 13, Issue 8 https://doi.org/10.1002/jcc.540130805	journal	October 1992
Particle mesh Ewald: An N ⋅log( N ) method for Ewald sums in large systems Darden, Tom; York, Darrin; Pedersen, Lee The Journal of Chemical Physics, Vol. 98, Issue 12 https://doi.org/10.1063/1.464397	journal	June 1993
A smooth particle mesh Ewald method Essmann, Ulrich; Perera, Lalith; Berkowitz, Max L. The Journal of Chemical Physics, Vol. 103, Issue 19 https://doi.org/10.1063/1.470117	journal	November 1995
The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals Zhao, Yan; Truhlar, Donald G. Theoretical Chemistry Accounts, Vol. 120, Issue 1-3 https://doi.org/10.1007/s00214-007-0310-x	journal	July 2007
Accuracy of Density Functionals in the Prediction of Electronic Proton Affinities of Amino Acid Side Chains Brás, Natércia F.; Perez, Marta A. S.; Fernandes, Pedro A. Journal of Chemical Theory and Computation, Vol. 7, Issue 12 https://doi.org/10.1021/ct200309v	journal	October 2011
Enzyme mechanisms with hybrid quantum and molecular mechanical potentials. I. Theoretical considerations Eurenius, Kirsten P.; Chatfield, David C.; Brooks, Bernard R. International Journal of Quantum Chemistry, Vol. 60, Issue 6 https://doi.org/10.1002/(SICI)1097-461X(1996)60:6<1189::AID-QUA7>3.0.CO;2-W	journal	January 1996
Optimization of parameters for semiempirical methods V: Modification of NDDO approximations and application to 70 elements Stewart, James J. P. Journal of Molecular Modeling, Vol. 13, Issue 12 https://doi.org/10.1007/s00894-007-0233-4	journal	September 2007
Can Semi-empirical Calculations Help Solve Mass Spectrometry Problems? Protonation Sites and Proton Affinities of Amino Acids Amorim Madeira, Paulo J.; Vaz, Pedro D.; Bettencourt da Silva, R. J. N. ChemPlusChem, Vol. 78, Issue 9 https://doi.org/10.1002/cplu.201300173	journal	August 2013
THE weighted histogram analysis method for free-energy calculations on biomolecules. I. The method Kumar, Shankar; Rosenberg, John M.; Bouzida, Djamal Journal of Computational Chemistry, Vol. 13, Issue 8 https://doi.org/10.1002/jcc.540130812	journal	October 1992
The calculation of the potential of mean force using computer simulations Roux, Benoît Computer Physics Communications, Vol. 91, Issue 1-3 https://doi.org/10.1016/0010-4655(95)00053-I	journal	September 1995
Mechanism of acyl transfer by the class A serine β-lactamase of Streptomyces albus G Lamotte-Brasseur, J.; Dive, G.; Dideberg, O. Biochemical Journal, Vol. 279, Issue 1 https://doi.org/10.1042/bj2790213	journal	October 1991
Engineering enzyme specificity by "substrate-assisted catalysis" Carter, P.; Wells, J. Science, Vol. 237, Issue 4813 https://doi.org/10.1126/science.3299704	journal	July 1987
Structural and Biochemical Evidence That a TEM-1 β-Lactamase N170G Active Site Mutant Acts via Substrate-assisted Catalysis Brown, Nicholas G.; Shanker, Sreejesh; Prasad, B. V. Venkataram Journal of Biological Chemistry, Vol. 284, Issue 48 https://doi.org/10.1074/jbc.M109.053819	journal	October 2009

Cited By (7)

Bifunctional nest-like self-floating microreactor for enhanced photothermal catalysis and biocatalysis Chi, Dechao; Sun, Dandan; Yang, Zekang Environmental Science: Nano, Vol. 6, Issue 12 https://doi.org/10.1039/c9en00968j	journal	January 2019
Neutron scattering in the biological sciences: progress and prospects Ashkar, Rana; Bilheux, Hassina Z.; Bordallo, Heliosa Acta Crystallographica Section D Structural Biology, Vol. 74, Issue 12 https://doi.org/10.1107/s2059798318017503	journal	December 2018
A suite-level review of the neutron single-crystal diffraction instruments at Oak Ridge National Laboratory Coates, L.; Cao, H. B.; Chakoumakos, B. C. Review of Scientific Instruments, Vol. 89, Issue 9 https://doi.org/10.1063/1.5030896	journal	September 2018
Dynamical Behavior of β-Lactamases and Penicillin- Binding Proteins in Different Functional States and Its Potential Role in Evolution Wang, Feng; Zhou, Hongyu; Wang, Xinlei Entropy, Vol. 21, Issue 11 https://doi.org/10.3390/e21111130	journal	November 2019
BraggNet: integrating Bragg peaks using neural networks Sullivan, Brendan; Archibald, Rick; Azadmanesh, Jahaun Journal of Applied Crystallography, Vol. 52, Issue 4 https://doi.org/10.1107/s1600576719008665	journal	July 2019
BraggNet: integrating Bragg peaks using neural networks Sullivan, Brendan; Archibald, Rick; Azadmanesh, Jahaun International Union of Crystallography (IUCr) https://doi.org/10.1107/s1600576719008665/fs5173sup2.pdf	text	January 2019
BraggNet: integrating Bragg peaks using neural networks Sullivan, Brendan; Archibald, Rick; Azadmanesh, Jahaun International Union of Crystallography (IUCr) https://doi.org/10.1107/s1600576719008665/fs5173sup1.pdf	text	January 2019