Systematic QM/MM Study for Predicting P NMR Chemical Shifts of Adenosine Nucleotides in Solution and Stages of ATP Hydrolysis in a Protein Environment

Overview

Journal J Chem Theory Comput

Publisher American Chemical Society

Specialties Biochemistry
Chemistry

Date 2024 Mar 18

PMID 38497488

Authors

Judit Katalin Szanto

Johannes C B Dietschreit

Mikhail Shein

Anne K Schutz

Christian Ochsenfeld

Affiliations

Soon will be listed here.

Abstract

NMR (nuclear magnetic resonance) spectroscopy allows for important atomistic insights into the structure and dynamics of biological macromolecules; however, reliable assignments of experimental spectra are often difficult. Herein, quantum mechanical/molecular mechanical (QM/MM) calculations can provide crucial support. A major problem for the simulations is that experimental NMR signals are time-averaged over much longer time scales, and since computed chemical shifts are highly sensitive to local changes in the electronic and structural environment, sufficiently large averages over representative structural ensembles are essential. This entails high computational demands for reliable simulations. For NMR measurements in biological systems, a nucleus of major interest is P since it is both highly present (e.g., in nucleic acids) and easily observable. The focus of our present study is to develop a robust and computationally cost-efficient framework for simulating P NMR chemical shifts of nucleotides. We apply this scheme to study the different stages of the ATP hydrolysis reaction catalyzed by p97. Our methodology is based on MM molecular dynamics (MM-MD) sampling, followed by QM/MM structure optimizations and NMR calculations. Overall, our study is one of the most comprehensive QM-based P studies in a protein environment and the first to provide computed NMR chemical shifts for multiple nucleotide states in a protein environment. This study sheds light on a process that is challenging to probe experimentally and aims to bridge the gap between measured and calculated NMR spectroscopic properties.

References

Berta D, Gehrke S, Nyiri K, Vertessy B, Rosta E . Mechanism-Based Redesign of GAP to Activate Oncogenic Ras. J Am Chem Soc. 2023; 145(37):20302-20310. PMC: 10515638. DOI: 10.1021/jacs.3c04330. View

Mader S, Lopez A, Lawatscheck J, Luo Q, Rutz D, Gamiz-Hernandez A . Conformational dynamics modulate the catalytic activity of the molecular chaperone Hsp90. Nat Commun. 2020; 11(1):1410. PMC: 7075974. DOI: 10.1038/s41467-020-15050-0. View

Benda L, Schneider B, Sychrovsky V . Calculating the response of NMR shielding tensor σ(31P) and 2J(31P,13C) coupling constants in nucleic acid phosphate to coordination of the Mg2+ cation. J Phys Chem A. 2011; 115(11):2385-95. DOI: 10.1021/jp1114114. View

Exner T, Frank A, Onila I, Moller H . Toward the Quantum Chemical Calculation of NMR Chemical Shifts of Proteins. 3. Conformational Sampling and Explicit Solvents Model. J Chem Theory Comput. 2015; 8(11):4818-27. DOI: 10.1021/ct300701m. View

Nagy G, Suardiaz R, Lopata A, Ozohanics O, Vekey K, Brooks B . Structural Characterization of Arginine Fingers: Identification of an Arginine Finger for the Pyrophosphatase dUTPases. J Am Chem Soc. 2016; 138(45):15035-15045. DOI: 10.1021/jacs.6b09012. View

Ochsenfeld C, Kussmann J, Koziol F . Ab initio NMR spectra for molecular systems with a thousand and more atoms: a linear-scaling method. Angew Chem Int Ed Engl. 2004; 43(34):4485-9. DOI: 10.1002/anie.200460336. View

Hayashi S, Ueno H, Shaikh A, Umemura M, Kamiya M, Ito Y . Molecular mechanism of ATP hydrolysis in F1-ATPase revealed by molecular simulations and single-molecule observations. J Am Chem Soc. 2012; 134(20):8447-54. DOI: 10.1021/ja211027m. View

Lymn R, Taylor E . Mechanism of adenosine triphosphate hydrolysis by actomyosin. Biochemistry. 1971; 10(25):4617-24. DOI: 10.1021/bi00801a004. View

Pavlikova Precechtelova J, Mladek A, Zapletal V, Hritz J . Quantum Chemical Calculations of NMR Chemical Shifts in Phosphorylated Intrinsically Disordered Proteins. J Chem Theory Comput. 2019; 15(10):5642-5658. DOI: 10.1021/acs.jctc.8b00257. View

10.

Kiani F, Fischer S . Stabilization of the ADP/metaphosphate intermediate during ATP hydrolysis in pre-power stroke myosin: quantitative anatomy of an enzyme. J Biol Chem. 2013; 288(49):35569-80. PMC: 3853302. DOI: 10.1074/jbc.M113.500298. View

11.

Case D, Cheatham 3rd T, Darden T, Gohlke H, Luo R, Merz Jr K . The Amber biomolecular simulation programs. J Comput Chem. 2005; 26(16):1668-88. PMC: 1989667. DOI: 10.1002/jcc.20290. View

12.

Zhang X, Shaw A, Bates P, NEWMAN R, Gowen B, Orlova E . Structure of the AAA ATPase p97. Mol Cell. 2001; 6(6):1473-84. DOI: 10.1016/s1097-2765(00)00143-x. View

13.

Bursch M, Mewes J, Hansen A, Grimme S . Best-Practice DFT Protocols for Basic Molecular Computational Chemistry. Angew Chem Int Ed Engl. 2022; 61(42):e202205735. PMC: 9826355. DOI: 10.1002/anie.202205735. View

14.

Mandala V, Loh D, Shepard S, Geeson M, Sergeyev I, Nocera D . Bacterial Phosphate Granules Contain Cyclic Polyphosphates: Evidence from P Solid-State NMR. J Am Chem Soc. 2020; 142(43):18407-18421. PMC: 7755298. DOI: 10.1021/jacs.0c06335. View

15.

Lacabanne D, Wiegand T, Di Cesare M, Orelle C, Ernst M, Jault J . Solid-State NMR Reveals Asymmetric ATP Hydrolysis in the Multidrug ABC Transporter BmrA. J Am Chem Soc. 2022; 144(27):12431-12442. PMC: 9284561. DOI: 10.1021/jacs.2c04287. View

16.

Glaves R, Mathias G, Marx D . Mechanistic insights into the hydrolysis of a nucleoside triphosphate model in neutral and acidic solution. J Am Chem Soc. 2012; 134(16):6995-7000. DOI: 10.1021/ja2101533. View

17.

Taylor E, Lymn R, Moll G . Myosin-product complex and its effect on the steady-state rate of nucleoside triphosphate hydrolysis. Biochemistry. 1970; 9(15):2984-91. DOI: 10.1021/bi00817a008. View

18.

Reynolds M, Hachicho C, Carl A, Gong R, Alushin G . Bending forces and nucleotide state jointly regulate F-actin structure. Nature. 2022; 611(7935):380-386. PMC: 9646526. DOI: 10.1038/s41586-022-05366-w. View

19.

Eastman P, Pande V . OpenMM: A Hardware Independent Framework for Molecular Simulations. Comput Sci Eng. 2015; 12(4):34-39. PMC: 4486654. DOI: 10.1109/MCSE.2010.27. View

20.

Kussmann J, Luenser A, Beer M, Ochsenfeld C . A reduced-scaling density matrix-based method for the computation of the vibrational Hessian matrix at the self-consistent field level. J Chem Phys. 2015; 142(9):094101. DOI: 10.1063/1.4908131. View