OPLS4: Improving Force Field Accuracy on Challenging Regimes of Chemical Space

Lü, Chao; Wu, Chuanjie; Ghoreishi, Delaram; Chen, Wei; Wang, Lingle; Damm, Wolfgang; Ross, Gregory A.; Dahlgren, Markus; Russell, Ellery; Bargen, Christopher D. Von; Abel, Robert; Friesner, Richard A.; Harder, Edward

doi:10.1021/acs.jctc.1c00302

Cited by 850 publications

(839 citation statements)

References 41 publications

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“…Only the mutated atoms was included in the REST "hot region" region. OPLS4 force field was used for the all simulations [20]. The obtained average structures from the simulations were used for the structural comparison on Figures 3A and 3B.…”

Section: Methodsmentioning

confidence: 99%

The High Transmission of SARS-CoV-2 Omicron (B.1.1.529) Variant is Not Only Due to Its hACE2 binding: A Free Energy of Perturbation Study

Fratev

2021

Preprint

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The mutations in the spike protein of SARS-CoV-2 Omicron variant (B.1.1.529 lineage) gave rise to questions, but the data on the mechanism of action at the molecular level is limited. In this study, we present the Free energy of perturbation (FEP) data about the RBD-hACE2 binding of this new variant. We identified two groups of mutations located close to the most contributing substitutions Q498R and Q493R, which altered significantly the RBD-hACE2 interactions. The Q498R, Y505H and G496S mutations, in addition to N501Y, highly increased the binding to hACE2. They enhanced the binding by 98, 14 and 13 folds, respectively, which transforms the S1-RBD to a picomolar binder. However, in contrast to the case in mice the Q493R/K mutations, in a combination with K417N and T478K, dramatically reduced the S1 RBD binding by over 100 folds. The N440K, G446S and T478K substitutions had lesser contribution. Thus, the total effect of these nine mutations located on the interaction surface of RBD-hACE2 turns out to be similar to that observed in the Alpha variant. In a special circumstances it could be further altered by the E484A and S477N mutations and even lower binding capacity is likely to be detected. Finally, we provide a structural basis of the observed changes in the interactions. These data may explain only partially the observed in South Africa extremely high Omicron spread and is in support to the hypothesis for multiple mechanisms of actions involved in the transmission.

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Section: Methodsmentioning

confidence: 99%

The High Transmission of SARS-CoV-2 Omicron (B.1.1.529) Variant is Not Only Due to Its hACE2 binding: A Free Energy of Perturbation Study

Fratev

2021

Preprint

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“…Only the mutated atoms was included in the REST "hot region" region. OPLS4 force field was used for the all simulations [18]. The obtained average structures from the simulations were used for the structural comparison on Figures 1 and 2.…”

Section: Methodsmentioning

confidence: 99%

The R346K Mutation in the Mu Variant of SARS-CoV-2 Alter the Interactions with Monoclonal Antibodies from Class 2: A Free Energy of Perturbation Study

Fratev

2021

Preprint

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The Mu variant of SARS-CoV-2 has been recently classified as a variant of interest (VOI) by the world health organization (WHO) but limited data are available at the moment. In particular, a special attention was given to the R346K mutation located in the receptor binding domain (RBD). In the current study we performed Free energy of perturbation (FEP) calculations to elucidate it possible impact on a set of neutralizing monoclonal antibodies (mAbs) which have been shown to be strong inhibitors of the most other known COVID-19 variants. Our results show that R346K affects the class 2 antibodies but its effect is not so significant (0.66 kcal/mol); i.e. reduces the binding with RBD about 3 times. An identical value was calculated also in the presence of both class 1 and class 2 antibodies (BD-812/836). Further, a similar reduction in the binding (0.4 kcal/mol) was obtained for BD-821/771 pair of mAbs. For comparison, the addition of K417N mutation, present in the newly registered Mu variant in July 2021 in UK, affected the class 1 mAbs by 1.29 kcal/mol reducing stronger the binding by about 10 times. Thus, the resistance effect of R346K mutation in the Mu variant is possible but not so significant and is due to the additional decrease of antibody neutralization based on the reduced binding of class 2 antibodies.

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“…During the simulations, the OPLS4 force field parameters were used and a cut-off radius of 9.0 Å was applied for analyzed short-range van der Waals and Coulomb interactions [ 48 ]. Nose-Hoover and Martyna-Tobias-Klein chain coupling scheme was used for the thermostat and barostat approaches, respectively [ 47 ].…”

Section: Methodsmentioning

confidence: 99%

Elucidating the Glucokinase Activating Potentials of Naturally Occurring Prenylated Flavonoids: An Explicit Computational Approach

et al. 2021

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Glucokinase activators are considered as new therapeutic arsenals that bind to the allosteric activator sites of glucokinase enzymes, thereby maximizing its catalytic rate and increasing its affinity to glucose. This study was designed to identify potent glucokinase activators from prenylated flavonoids isolated from medicinal plants using molecular docking, molecular dynamics simulation, density functional theory, and ADMET analysis. Virtual screening was carried out on glucokinase enzymes using 221 naturally occurring prenylated flavonoids, followed by molecular dynamics simulation (100 ns), density functional theory (B3LYP model), and ADMET (admeSar 2 online server) studies. The result obtained from the virtual screening with the glucokinase revealed arcommunol B (−10.1 kcal/mol), kuwanon S (−9.6 kcal/mol), manuifolin H (−9.5 kcal/mol), and kuwanon F (−9.4 kcal/mol) as the top-ranked molecules. Additionally, the molecular dynamics simulation and MM/GBSA calculations showed that the hit molecules were stable at the active site of the glucokinase enzyme. Furthermore, the DFT and ADMET studies revealed the hit molecules as potential glucokinase activators and drug-like candidates. Our findings suggested further evaluation of the top-ranked prenylated flavonoids for their in vitro and in vivo glucokinase activating potentials.

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OPLS4: Improving Force Field Accuracy on Challenging Regimes of Chemical Space

Cited by 850 publications

References 41 publications

The High Transmission of SARS-CoV-2 Omicron (B.1.1.529) Variant is Not Only Due to Its hACE2 binding: A Free Energy of Perturbation Study

The High Transmission of SARS-CoV-2 Omicron (B.1.1.529) Variant is Not Only Due to Its hACE2 binding: A Free Energy of Perturbation Study

The R346K Mutation in the Mu Variant of SARS-CoV-2 Alter the Interactions with Monoclonal Antibodies from Class 2: A Free Energy of Perturbation Study

Elucidating the Glucokinase Activating Potentials of Naturally Occurring Prenylated Flavonoids: An Explicit Computational Approach

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