Rational Redesign of Enzyme via the Combination of Quantum Mechanics/Molecular Mechanics, Molecular Dynamics, and Structural Biology Study

Hong-Yan Lin ◽  
Xi Chen ◽  
Jin Dong ◽  
Jing-Fang Yang ◽  
Han Xiao ◽  
2015 ◽  
Vol 112 (37) ◽  
pp. 11571-11576 ◽  
Vivek Sharma ◽  
Galina Belevich ◽  
Ana P. Gamiz-Hernandez ◽  
Tomasz Róg ◽  
Ilpo Vattulainen ◽  

Complex I functions as a redox-linked proton pump in the respiratory chains of mitochondria and bacteria, driven by the reduction of quinone (Q) by NADH. Remarkably, the distance between the Q reduction site and the most distant proton channels extends nearly 200 Å. To elucidate the molecular origin of this long-range coupling, we apply a combination of large-scale molecular simulations and a site-directed mutagenesis experiment of a key residue. In hybrid quantum mechanics/molecular mechanics simulations, we observe that reduction of Q is coupled to its local protonation by the His-38/Asp-139 ion pair and Tyr-87 of subunit Nqo4. Atomistic classical molecular dynamics simulations further suggest that formation of quinol (QH2) triggers rapid dissociation of the anionic Asp-139 toward the membrane domain that couples to conformational changes in a network of conserved charged residues. Site-directed mutagenesis data confirm the importance of Asp-139; upon mutation to asparagine the Q reductase activity is inhibited by 75%. The current results, together with earlier biochemical data, suggest that the proton pumping in complex I is activated by a unique combination of electrostatic and conformational transitions.

2012 ◽  
Vol 34 (9) ◽  
pp. 750-756 ◽  
Marcin Nowosielski ◽  
Marcin Hoffmann ◽  
Aneta Kuron ◽  
Malgorzata Korycka-Machala ◽  
Jaroslaw Dziadek

Mauro Boero ◽  
Masaru Tateno

This article describes quantum methods used to study proteins and nucleic acids: Hartree–Fock all-electron approaches, density-functional theory approaches, and hybrid quantum-mechanics/molecular-mechanics approaches. In addition to an analysis of the electronic structure, quantum-mechanical approaches for simulating proteins and nucleic acids can elucidate the cleavage and formation of chemical bonds in biochemical reactions. This presents a computational challenge, and a number of methods have been proposed to overcome this difficulty, including enhanced temperature methods such as high-temperature molecular dynamics, parallel tempering and replica exchange. Alternative methods not relying on the knowledge a priori of the final products make use of biasing potentials to push the initial system away from its local minimum and to enhance the sampling of the free-energy landscape. This article considers two of these biasing techniques, namely Blue Moon and metadynamics.

Walker M. Jones ◽  
Aaron G. Davis ◽  
R. Hunter Wilson ◽  
Katherine L. Elliott ◽  
Isaiah Sumner

We present classical molecular dynamics (MD), Born-Oppenheimer molecular dynamics (BOMD), and hybrid quantum mechanics/molecular mechanics (QM/MM) data. MD was performed using the GPU accelerated pmemd module of the AMBER14MD package. BOMD was performed using CP2K version 2.6. The reaction rates in BOMD were accelerated using the Metadynamics method. QM/MM was performed using ONIOM in the Gaussian09 suite of programs. Relevant input files for BOMD and QM/MM are available.

2020 ◽  
Prasanth Babu Ganta ◽  
Oliver Kühn ◽  
Ashour A. Ahmed

Today's fertilizers rely heavily on mining phosphorus (P) rocks. These rocks are known to become exhausted in near future and hence, effective P use is crucial to avoid food shortage. A substantial amount of P from fertilizers gets adsorbed onto soil minerals to become unavailable to plants. Understanding P interaction with these minerals would help efforts that improve P efficiency. To this end we performed a molecular level analysis of the interaction of common organic P compounds (glycerolphosphate [GP] & inositol hexaphosphate [IHP]) with the abundant soil mineral (goethite) in presence of water. Molecular dynamics simulations are performed for goethite-IHP/GP-water complexes using the multiscale quantum mechanics/molecular mechanics method. Results show that GP forms monodentate (M) and bidentate mononuclear (B) motifs with B being more stable than M. IHP interacts through multiple phosphate groups with the \textbf{3M} motif being most stable. The order of goethite-IHP/GP interaction energies is: GP M < GP B < IHP M < IHP 3M. Water is important in these interactions as multiple proton transfers occur and hydrogen bonds are formed between goethite--IHP/GP complexes and water. We also present theoretically calculated infrared spectra which match reasonably well with frequencies reported in literature.

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