The Impact of Electron Correlation on Describing QM/MM Interactions in the Attendant Molecular Dynamics Simulations of CO in Myoglobin

Abstract

well by the QM/MM method using the electrostatic embedding approach 16. This is as expected, because most of the protein functions are primarily achieved by the electrostatic 17-21. For example, as previous works demonstrate, the electric field that a protease exerts at the active site is one of the most important origins of its catalytic power 22-26. With the advances in computer hardware and computational methods 27-31 , a number of QM/MM molecular dynamics (MD) studies employing various implementations of the expensive (prohibitive time/computational costs) Møller-Plesset perturbation theory (MP2) have been conducted 32-43. However, it remains challenging to apply potentially highly accurate correlated ab initio QM methods (e.g., coupled clustering) in QM/MM MD simulations with a large number of QM atoms. Therefore, semi-empirical, DFT, or even Hatree-Fock (HF) methods have been employed in most QM/MM studies. However, DFT and HF methods suffer from a well-known limitation; that is, the Coulomb correlation is missing in the mean-field HF approach, which results in its inability to account for the dispersion effects, whereas many DFT-based QM methods cannot account for these effects in precise terms because the exact correlation functional is unknown 44,45. Consequently, DFT methods do not always provide correct results in QM/MM simulations 46-49 , whereas HF method can only work well in the QM/ MM simulation of specific systems (e.g., methyl-transfer reactions) 50. Great efforts have been made to account for the dispersion effects in QM methods over the past decade, with a number of empirical dispersion methods routinely used for the QM calculations 45,51-53. The inclusion of the electron correlation and dispersion effects is mandatory for QM studies related to chemical systems and various intramolecular phenomena 27,44. Investigation of the importance of these effects on the accurate description of the QM/MM interactions is a primary issue for realistic MD simulations of large or condensed systems with a QM/MM protocol. For this, first, an appropriate model system is required. Such a system should have a characteristic quantity (e.g., reaction barriers) that is easily handled by the QM/MM simulation with a small-sized QM region to facilitate the convergence of the simulation, and the characteristic quantity should be sensitive to the electrostatic interactions. It is preferable not to have dangling bonds between the QM and MM subsystems to avoid introducing unnecessary effects from the QM/MM boundary 54. The MbCO system is one of the most studied proteins for investigating ligand binding, migration or other biologically relevant processes 55-74. The spectroscopic characterization of CO has been used to explore the relationship between the dynamics, structure, and function of proteins in numerous experimental studies 63,71,73-75. The molecular migration pathway for the CO to leave the myoglobin involves a set of transition steps between certain specific cavities, including the so-called distal heme pocket (the...

Assessment of an Electrostatic Energy-Based Charge Model for Modeling the Electrostatic Interactions in Water Solvent

“…Similar to the EEC-QF model, previous studies have shown that ESP-derived charges for a chemical bond exhibit a linear relationship with the electric field along the bond . Therefore, it is expected that the predicted EIs of ESP-derived charges will follow a quadratic function relationship with different environments (or electric fields).…”

“…Similar to the EEC-QF model, previous studies have shown that ESP-derived charges for a chemical bond exhibit a linear relationship with the electric field along the bond. 121 Therefore, it is expected that the predicted EIs of ESP-derived charges will follow a quadratic function relationship with different environments (or electric fields). The relationship between the ESP-derived charges and the electric field for the O−H bond is depicted in Figure 4C, with the best-fit line given by the equation q H ESP =0.00052805|E ⃗ OH | + 0.39882 (the units of q H ESP and |E ⃗ OH | were in e and MV/cm, respectively).…”

Best Practices on QM/MM Simulations of Biological Systems

“…Among them, heme proteins, the family of proteins containing an iron–porphyrin complex as a prosthetic group, were widely studied using QM/MM methodologies, especially in order to obtain information on ligand binding ,, and catalysis. ,, Particularly the globin family is one of the most studied, including the well-known mammalian hemoglobin and myoglobin, widely used as reference systems for both computational and experimental method developments. Globins are able to bind (and perform reactions) with small ligands such as O 2 , NO, and CO, as well as other reactive oxygen and nitrogen species (RNOS), and given the extensive structural and spectroscopic available data in a wide variety of conformational and ligand bound states, such as the paradigmatic CO bound myoglobin, they have been extensively studied using QM/MM strategies. ,− …”

Stationary and Time-Dependent Carbon Monoxide Stretching Mode Features in Carboxy Myoglobin: A Theoretical–Computational Reappraisal

“…The binding of carbon monoxide (CO), and more in general of small molecules, to the sixth coordination site of iron­(II) in the heme prosthetic group of myoglobin − (both horse-heart and sperm-whale) has received a great deal of attention from basic research. A huge number of fundamental studies, focused on a large variety of structural, spectroscopic, thermodynamic, and kinetic aspects has been indeed devoted to carboxymyoglobin (MbCO) and oxymyoglobin (MbO2), as well as their mutants, both experimentally − and computationally. − In this context, the stationary and time-dependent infrared (IR) spectral behavior of the heme-bound CO stretching frequencies was particularly interesting , i.e., both the behavior associated with the Fe–C mode (hereafter ν Fe–C ) and the one associated with C–O mode (hereafter ν CO ), whose spectral signal interpretation turned out to be crucial for understanding the mechanisms underlying the binding differences between CO and O 2 to iron­(II). − Specifically, the IR signal of ν CO in MbCO is characterized by three different substates, denoted as A 0 (≃1965 cm –1 ), A 1 (≃1945 cm –1 ), and A 3 (≃1934 cm –1 ), also showing other relevant features such as different CO rebinding rates, different dephasing rates, and different sensitivities to pH . A fourth substate, usually indicated as A x , appears as scarcely relevant in physiological conditions.…”