Hydrogen Bonding in Human P450-Substrate Interactions: A Major Contribution to Binding Affinity

Lewis, David F.

doi:10.1100/tsw.2004.210

Cited by 18 publications

(15 citation statements)

References 16 publications

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“…To form these intramolecular H-bonds, polypeptide chains need to escape from hydrogen bonding with the surrounding strong polar water molecules. Binding energy (hydrogen bond energy) of the H-bonds between the N-H groups and C=O groups of the main chain in secondary structures is about −3.47 kcal/mol [32,33], whereas binding energy of the H-bonds between the N-H groups and water molecules is about −7.65 kcal/mol and binding energy between the C=O groups and water molecules is about −4.7 kcal/mol [32,[34][35][36][37]. Thus, the calculated ∆H for the formation of a hydrogen bond between the N-H groups and C=O groups of the main chain in water is about 2.7 kcal/mol.…”

Section: Resultsmentioning

confidence: 99%

Entropy-Enthalpy Compensations Fold Proteins in Precise Ways

Hou

et al. 2021

IJMS

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Exploring the protein-folding problem has been a longstanding challenge in molecular biology and biophysics. Intramolecular hydrogen (H)-bonds play an extremely important role in stabilizing protein structures. To form these intramolecular H-bonds, nascent unfolded polypeptide chains need to escape from hydrogen bonding with surrounding polar water molecules under the solution conditions that require entropy-enthalpy compensations, according to the Gibbs free energy equation and the change in enthalpy. Here, by analyzing the spatial layout of the side-chains of amino acid residues in experimentally determined protein structures, we reveal a protein-folding mechanism based on the entropy-enthalpy compensations that initially driven by laterally hydrophobic collapse among the side-chains of adjacent residues in the sequences of unfolded protein chains. This hydrophobic collapse promotes the formation of the H-bonds within the polypeptide backbone structures through the entropy-enthalpy compensation mechanism, enabling secondary structures and tertiary structures to fold reproducibly following explicit physical folding codes and forces. The temperature dependence of protein folding is thus attributed to the environment dependence of the conformational Gibbs free energy equation. The folding codes and forces in the amino acid sequence that dictate the formation of β-strands and α-helices can be deciphered with great accuracy through evaluation of the hydrophobic interactions among neighboring side-chains of an unfolded polypeptide from a β-strand-like thermodynamic metastable state. The folding of protein quaternary structures is found to be guided by the entropy-enthalpy compensations in between the docking sites of protein subunits according to the Gibbs free energy equation that is verified by bioinformatics analyses of a dozen structures of dimers. Protein folding is therefore guided by multistage entropy-enthalpy compensations of the system of polypeptide chains and water molecules under the solution conditions.

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Section: Resultsmentioning

confidence: 99%

Entropy-Enthalpy Compensations Fold Proteins in Precise Ways

Hou

et al. 2021

IJMS

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“…These hydrophilic CO and NH groups are hydrogen-bonded with the surrounding water molecules in a hydration shell before the docking. The binding energy of the H-bond between the NH group and a water molecule is about −7.65 kcal/mol (32,000 J/mol), and the binding bond energy of the H-bond between the CO group and a water molecule is about −4.66 kcal/mol (19,479 J/mol) [38][39][40][41][42]. Note that after a water molecule loses its hydrogen bonding with the hydrophilic group of a protein, other water molecules are able to saturate the H-bond formations of the water molecule in an aqueous solution as part of the compensation for the enthalpy change, taking the average as about ∆H = 12,000 J/mol per removed hydrogen-bonded water molecule (i.e., an H-bond) from a hydrophilic surface area.…”

Section: Docking Between the Hydrophobic Surface Area And The Hydrophilic Surface Areamentioning

confidence: 99%

“…After a water molecule loses the hydrogen bonding with the hydrophilic group of a protein, other water molecules are able to saturate the H-bond formations of the water molecule. The binding energy of the H-bond between the NH group and a water molecule is about −7.65 kcal/mol, and the binding bond energy of the H-bond between the CO group and a water molecule is about −4.66 kcal/mol [38][39][40][41][42]. Similarly, the average of about ∆H = 12,000 J/mol per removed hydrogen-bonded water molecule is taken from a hydrophilic surface area.…”

Section: Docking-induced Attractive Dipole-dipole Interactionmentioning

confidence: 99%

“…When using the change of Gibbs free energy to assess the spontaneity of protein-protein docking, it is important to emphasize that the definition of enthalpy and entropy apply to the whole system of proteins and the surrounding water molecules [32]. Water molecules (i.e., hydration shell) are able to saturate the hydrogen (H)-bond formations of the hydrophilic groups on the protein surface before protein-protein docking [33][34][35] because water molecules have strong hydrogen bonding interactions [35][36][37][38][39][40][41][42][43]. The hydration shell (i.e., hydration layer) around a protein has been experimentally found to possess dynamics that is distinct from the bulk water at a distance of 1 nm, and water molecules slow down greatly when they enter the hydration shell of a protein [33,44].…”

Section: Introductionmentioning

confidence: 99%

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SARS-CoV-2 Variants, RBD Mutations, Binding Affinity, and Antibody Escape

Yang

Guo

et al. 2021

IJMS

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Since 2020, the receptor-binding domain (RBD) of the spike protein of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been constantly mutating, producing most of the notable missense mutations in the context of “variants of concern”, probably in response to the vaccine-driven alteration of immune profiles of the human population. The Delta variant, in particular, has become the most prevalent variant of the epidemic, and it is spreading in countries with the highest vaccination rates, causing the world to face the risk of a new wave of the contagion. Understanding the physical mechanism responsible for the mutation-induced changes in the RBD’s binding affinity, its transmissibility, and its capacity to escape vaccine-induced immunity is the “urgent challenge” in the development of preventive measures, vaccines, and therapeutic antibodies against the coronavirus disease 2019 (COVID-19) pandemic. In this study, entropy–enthalpy compensation and the Gibbs free energy change were used to analyze the impact of the RBD mutations on the binding affinity of SARS-CoV-2 variants with the receptor angiotensin converting enzyme 2 (ACE2) and existing antibodies. Through the analysis, we found that the existing mutations have already covered almost all possible detrimental mutations that could result in an increase of transmissibility, and that a possible mutation in amino-acid position 498 of the RBD can potentially enhance its binding affinity. A new calculation method for the binding energies of protein–protein complexes is proposed based on the entropy–enthalpy compensation rule. All known structures of RBD–antibody complexes and the RBD–ACE2 complex comply with the entropy–enthalpy compensation rule in providing the driving force behind the spontaneous protein–protein docking. The variant-induced risk of breakthrough infections in vaccinated people is attributed to the L452R mutation’s reduction of the binding affinity of many antibodies. Mutations reversing the hydrophobic or hydrophilic performance of residues in the spike RBD potentially cause breakthrough infections of coronaviruses due to the changes in geometric complementarity in the entropy–enthalpy compensations between antibodies and the virus at the binding sites.

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“…They may alternatively have additional interaction sites with the enzyme which are not covered by our model. For very small (1) phenacetin (2) amitriptyline (3) clozapine (4) cyclobenzaprine (5) estradiol (6) haloperidol (7) imipramine (8) mexiletine (9) naproxen (10) olanzapine (11) ondansetron (12) propranolol (13) riluzole (14) ropivacaine (15) tacrine (16) theophylline (17) tizanidine (18) compounds like mexiletine (9), it might not be necessary to occupy all three interaction spheres to be recognized and metabolized by P450 1A2.…”

Section: Ligand-based General Model For P450 1a2 Substratesmentioning

confidence: 99%

Development and Validation of an In Silico P450 Profiler Based on Pharmacophore Models

Schuster

Laggner²,

Steindl³

et al. 2006

CDDT

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In today's drug discovery process, the very early consideration of ADME properties is aimed at a reduction of drug candidate drop out rate in later development stages. Apart from in vitro testing, in silico methods are evaluated as complementary screening tools for compounds with unfavorable ADME attributes. Especially members of the cytochrome P450 (P450) enzyme superfamily-- e.g. P450 1A2, P450 2C9, P450 2C19, P450 2D6, and P450 3A4-- contribute to xenobiotic metabolism, and compound interaction with one of these enzymes is therefore critically evaluated. Pharmacophore models are widely used to identify common features amongst ligands for any target. In this study, both structure-based and ligand-based models for prominent drug-metabolizing members of the P450 family were generated employing the software packages LigandScout and Catalyst. Essential chemical ligand features for substrate and inhibitor activity for all five P450 enzymes investigated were determined and analyzed. Finally, a collection of 11 pharmacophores for substrates and inhibitors was evaluated as an in silico P450 profiling tool that could be used for early ADME estimation of new chemical entities.

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Hydrogen Bonding in Human P450-Substrate Interactions: A Major Contribution to Binding Affinity

Cited by 18 publications

References 16 publications

Entropy-Enthalpy Compensations Fold Proteins in Precise Ways

Entropy-Enthalpy Compensations Fold Proteins in Precise Ways

SARS-CoV-2 Variants, RBD Mutations, Binding Affinity, and Antibody Escape

Development and Validation of an In Silico P450 Profiler Based on Pharmacophore Models

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