A Computational Exercise Illustrating Molecular Vibrations and Normal Modes

Rempe, Susan B.; Jónsson, Hannes

doi:10.1007/s00897980231a

Cited by 36 publications

(22 citation statements)

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“…Practitioners who use harmonic approximations of the potential energy surface anticipate this error. 54 Our previous studies have thus considered small ion-ligand distances for QCT analysis. 18,19,21–23 If this is not done, the problem of multiple, anharmonic minima arises, and less satisfactory results are obtained.…”

Section: Resultsmentioning

confidence: 99%

Probing the Thermodynamics of Competitive Ion Binding Using Minimum Energy Structures

2011

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Ion binding is known to affect the properties of biomolecules and is directly involved in many biochemical pathways. Because of the highly polar environments where such ions are found, a quantum-mechanical treatment is preferable for understanding the energetics of competitive ion binding. Due to computational cost, a quantum mechanical treatment may involve several approximations, however, whose validity can be difficult to determine. Using thermodynamic cycles, we show how intuitive models for complicated ion binding reactions can be built up from simplified, isolated ion-ligand binding site geometries suitable for quantum mechanical treatment. First the ion binding free energies of individual, minimum energy structures determine their intrinsic ion selectivities. Next, the relative propensity for each minimum energy structure is determined locally from the balance of ion-ligand and ligand-ligand interaction energies. Finally, the environment external to the binding site exerts its influence both through long-ranged dispersive and electrostatic interactions with the binding site as well as indirectly through shifting the binding site compositional and structural preferences. The resulting picture unifies field-strength, topological control, and phase activation viewpoints into a single theory that explicitly indicates the important role of solute coordination state on overall reaction energetics. As an example, we show that the Na+ →K+ selectivities can be recovered by correctly considering the conformational contribution to the selectivity. This can be done even when constraining configuration space to the neighborhood around a single, arbitrarily chosen, minimum energy structure. Structural regions around minima for K+- and Na+-water clusters are exhibited that display both rigid/mechanical and disordered/entropic selectivity mechanisms for both Na+ and K+. Thermodynamic consequences of the theory are discussed with an emphasis on the role of coordination structure in determining experimental properties of ions in complex biological environments.

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Section: Resultsmentioning

confidence: 99%

Probing the Thermodynamics of Competitive Ion Binding Using Minimum Energy Structures

2011

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“…The configurational entropy was calculated using the normal mode analysis (NMA) method (Karplus and Kushick, 1981 ; Rempe and Jónsson, 1998 ; Xu et al, 2011 ), and ~300 snapshots were used in the calculation due to high computational cost. Each configuration was energy minimized in an implicit solvent (nmode_igb = 1) using a maximum of 50,000 steps, and a target root-mean-square gradient of 10 −4 kcal mol −1 Å −1 via mmpbsa_py_nabnmode (Hawkins et al, 1995 , 1996 ; Kar and Knecht, 2012a , b , c ; Kar et al, 2013 ).…”

Section: Methodsmentioning

confidence: 99%

Computational Investigation of Structural Dynamics of SARS-CoV-2 Methyltransferase-Stimulatory Factor Heterodimer nsp16/nsp10 Bound to the Cofactor SAM

Jonniya

Roy

et al. 2020

Front. Mol. Biosci.

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Recently, a highly contagious novel coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has emerged, posing a global threat to public health. Identifying a potential target and developing vaccines or antiviral drugs is an urgent demand in the absence of approved therapeutic agents. The 5′-capping mechanism of eukaryotic mRNA and some viruses such as coronaviruses (CoVs) are essential for maintaining the RNA stability and protein translation in the virus. SARS-CoV-2 encodes S-adenosyl-L-methionine (SAM) dependent methyltransferase (MTase) enzyme characterized by nsp16 (2′-O-MTase) for generating the capped structure. The present study highlights the binding mechanism of nsp16 and nsp10 to identify the role of nsp10 in MTase activity. Furthermore, we investigated the conformational dynamics and energetics behind the binding of SAM to nsp16 and nsp16/nsp10 heterodimer by employing molecular dynamics simulations in conjunction with the Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) method. We observed from our simulations that the presence of nsp10 increases the favorable van der Waals and electrostatic interactions between SAM and nsp16. Thus, nsp10 acts as a stimulator for the strong binding of SAM to nsp16. The hydrophobic interactions were predominately identified for the nsp16-nsp10 interactions. Also, the stable hydrogen bonds between Ala83 (nsp16) and Tyr96 (nsp10), and between Gln87 (nsp16) and Leu45 (nsp10) play a vital role in the dimerization of nsp16 and nsp10. Besides, Computational Alanine Scanning (CAS) mutagenesis was performed, which revealed hotspot mutants, namely I40A, V104A, and R86A for the dimer association. Hence, the dimer interface of nsp16/nsp10 could also be a potential target in retarding the 2′-O-MTase activity in SARS-CoV-2. Overall, our study provides a comprehensive understanding of the dynamic and thermodynamic process of binding nsp16 and nsp10 that will contribute to the novel design of peptide inhibitors based on nsp16.

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“…Anharmonicity may arise because of the weak interactions between the solute and water ligands as well as hydrogen bonding between water molecules that lead to large atomic displacements. 56,57 Hydrophobic molecules, unlike ions that have strong interactions with water and relatively low coordination numbers, often form weakly bound clusters with several water molecules, causing considerable anharmonicity in vibrations of the system. 16,33,34,58 That said, we can reduce the anharmonicity of our system by shrinking the observation volume to allow fewer water molecules in the inner-shell cluster with CO 2 .…”

Section: Inner-shell Gas Phase Calculationmentioning

confidence: 99%

CO2 solvation free energy using quasi-chemical theory

Jiao

Rempe

2011

The Journal of Chemical Physics

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Accumulation of greenhouse gases, especially carbon dioxide, is believed to be the key factor in global climate change. To develop effective ways to remove CO(2) from the atmosphere, it is helpful to understand the mechanism of CO(2) solvation first. Here we investigate the thermodynamics of CO(2) hydration using quasi-chemical theory. Two approaches for estimating hydration free energy are carried out. Both agree reasonably well with experimental measurements. Analysis of the free energy components reveals that the weak hydration free energy results from a balance of unfavorable molecular packing and favorable chemical association.

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A Computational Exercise Illustrating Molecular Vibrations and Normal Modes

Cited by 36 publications

References 0 publications

Probing the Thermodynamics of Competitive Ion Binding Using Minimum Energy Structures

Probing the Thermodynamics of Competitive Ion Binding Using Minimum Energy Structures

Computational Investigation of Structural Dynamics of SARS-CoV-2 Methyltransferase-Stimulatory Factor Heterodimer nsp16/nsp10 Bound to the Cofactor SAM

CO2 solvation free energy using quasi-chemical theory

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