Some mechanistic underpinnings of molecular adaptations of SARS-COV-2 spike protein by integrating candidate adaptive polymorphisms with protein dynamics DOI Creative Commons
Nicholas J. Ose, Paul Campitelli, Tushar Modi

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 15, 2023

We integrate evolutionary predictions based on the neutral theory of molecular evolution with protein dynamics to generate mechanistic insight into adaptations SARS-COV-2 Spike (S) protein. With this approach, we first identified Candidate Adaptive Polymorphisms (CAPs) SARS-CoV-2 and assessed impact these CAPs through analysis. Not only have found that frequently overlap well-known functional sites, but also, using several different dynamics-based metrics, reveal critical allosteric interplay between S binding sites human ACE2 (hACE2) interact far differently hACE2 site residues in open conformation compared closed form. In particular, CAP control state, suggesting an binding. also explored characteristic mutations strains find dynamic hallmarks potential effects future mutations. Our analyses Delta strain-specific variants non-additive (i.e., epistatic) interactions whereas less pathogenic Omicron mostly additive Finally, our analysis suggests novel observed strain epistatically help escape antibody

Language: Английский

A slow but steady nanoLuc: R162A mutation results in a decreased, but stable, nanoLuc activity DOI Creative Commons
Wesam S. Ahmed,

Anupriya M. Geethakumari,

Asfia Sultana

et al.

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 269, P. 131864 - 131864

Published: April 29, 2024

NanoLuc (NLuc) luciferase has found extensive application in designing a range of biological assays, including gene expression analysis, protein-protein interaction, and protein conformational changes due to its enhanced brightness small size. However, questions related mechanism interaction with the substrate, furimazine, as well bioluminescence activity remain elusive. Here, we combined molecular dynamics (MD) simulation mutational analysis show that R162A mutation results decreased but stable NLuc living cells vitro. Specifically, performed multiple, all-atom, explicit solvent MD simulations apo furimazine-docked (holo) structures revealing differential absence presence ligand. Further, trajectories for hydrogen bonds (H-bonds) formed between furimazine revealed substantial H-bond R162 Q32 residues. Mutation two residues R162A, not Q32A, mutant live cell vitro assays using lysates prepared from expressing proteins substrate. In addition highlighting role residue activity, believe will find wide requiring extended monitoring activity. Bioluminescence been extensively utilized developing variety biomedical assays. this regard, engineering brighter bioluminescent proteins, i.e. luciferases, played significant role. This is acutely exemplified by luciferase, which size displays much thermal stability compared previously available luciferases. While desirable multitude it would also be useful develop variants display prolonged specifically relevant require periods, such case biosensors designed slow enzymatic or cellular signaling reactions, without necessitating multiple rounds substrate any specialized reagents result increased assay costs. current manuscript, report possesses albeit lower than wild-type NLuc, envisage wider slower events.

Language: Английский

Citations

5
Some mechanistic underpinnings of molecular adaptations of SARS-COV-2 spike protein by integrating candidate adaptive polymorphisms with protein dynamics DOI Creative Commons
Nicholas J. Ose, Paul Campitelli, Tushar Modi

et al.

eLife, Journal Year: 2024, Volume and Issue: 12

Published: May 7, 2024

We integrate evolutionary predictions based on the neutral theory of molecular evolution with protein dynamics to generate mechanistic insight into adaptations SARS-COV-2 spike (S) protein. With this approach, we first identified candidate adaptive polymorphisms (CAPs) SARS-CoV-2 S and assessed impact these CAPs through analysis. Not only have found that frequently overlap well-known functional sites, but also, using several different dynamics-based metrics, reveal critical allosteric interplay between binding sites human ACE2 (hACE2) interact far differently hACE2 site residues in open conformation compared closed form. In particular, CAP control state, suggesting an binding. also explored characteristic mutations strains find dynamic hallmarks potential effects future mutations. Our analyses Delta strain-specific variants non-additive (i.e., epistatic) interactions whereas less pathogenic Omicron mostly additive Finally, our analysis suggests novel observed strain epistatically help escape antibody

Language: Английский

Citations

4
GRP78 and cell-surface GRP78 self-association; In silico perspective DOI
Abdo A. Elfiky, Alaa M. Elgohary

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: 307, P. 141844 - 141844

Published: March 7, 2025

Language: Английский

Citations

0
Subtle Changes at the RBD/hACE2 Interface During SARS-CoV-2 Variant Evolution: A Molecular Dynamics Study DOI Creative Commons
Aria Gheeraert, Vincent Leroux, Dominique Mias‐Lucquin

et al.

Biomolecules, Journal Year: 2025, Volume and Issue: 15(4), P. 541 - 541

Published: April 7, 2025

The SARS-CoV-2 Omicron variants show different behavior compared to the previous variants, especially with respect Delta variant, which promotes a lower morbidity despite being much more contagious. In this perspective, we performed molecular dynamics (MD) simulations of spike RBD/hACE2 complexes corresponding WT, and four variants. Carrying out comprehensive analysis residue interactions within between two partners allowed us draw profile each variant by using complementary methods (PairInt, hydrophobic potential, contact PCA). PairInt calculations highlighted residues most involved in electrostatic interactions, make strong contribution binding highly stable RBD hACE2. Apolar contacts made substantial detection patches. Contact networks cross-correlation matrices were able detect subtle changes at point mutations as S375F mutation occurring all is likely confer an advantage stability. This study brings new highlights on dynamic hACE2, may explain final persistence over Delta.

Language: Английский

Citations

0
Viral entry mechanisms: the role of molecular simulation in unlocking a key step in viral infections DOI Creative Commons
Mariana Valério, Carolina C. Buga, Manuel N. Melo

et al.

FEBS Open Bio, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 14, 2024

Viral infections are a major global health concern, affecting millions of people each year. entry is one the crucial stages in infection process, but its details remain elusive. Enveloped viruses enclosed by lipid membrane that protects their genetic material and these linked to various human illnesses, including influenza, COVID‐19. Due advancements made field molecular simulation, significant progress has been unraveling dynamic processes involved viral enveloped viruses. Simulation studies have provided deep insight into function proteins responsible for attaching host receptors promoting fusion (fusion proteins), deciphering interactions between receptors, shedding light on functional significance key regions, such as peptide. These already significantly contributed our understanding this critical aspect assisted development effective strategies combat diseases improve health. This review focuses vital role facilitating process highlights contributions simulation uncover underlying mechanisms action.

Language: Английский

Citations

2
Mechanistic study of the transmission pattern of the SARS‐CoV‐2 omicron variant DOI Creative Commons
Ke An,

Xianzhi Yang,

Mengqi Luo

et al.

Proteins Structure Function and Bioinformatics, Journal Year: 2024, Volume and Issue: 92(6), P. 705 - 719

Published: Jan. 5, 2024

Abstract The omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) characterized by 30 mutations in its spike protein, has rapidly spread worldwide since November 2021, significantly exacerbating the ongoing COVID‐19 pandemic. In order to investigate relationship between these and variant's high transmissibility, we conducted a systematic analysis mutational effect on spike–angiotensin‐converting enzyme‐2 (ACE2) interactions explored structural/energy correlation key mutations, utilizing reliable coarse‐grained model. Our study extended beyond receptor‐binding domain (RBD) trimer through comprehensive modeling full‐length rather than just RBD. free‐energy calculation revealed that enhanced binding affinity protein ACE2 receptor is correlated with increased structural stability isolated thus explaining heightened transmissibility. conclusion was supported our experimental analyses involving expression purification trimer. Furthermore, energy decomposition established those electrostatic make major contributions this effect. We categorized into four groups an analytical framework can be employed studying future mutations. Additionally, calculations rationalized reduced towards most available therapeutic neutralizing antibodies, when compared wild type. By providing concrete data offering solid explanation, contributes better understanding theories observations lays foundation for investigations.

Language: Английский

Citations

1
Prediction of the binding location between the nuclear inhibitor of DNA binding and differentiation 2 (ID2) and HSPA5 DOI
Abdo A. Elfiky

Pathology - Research and Practice, Journal Year: 2024, Volume and Issue: 255, P. 155217 - 155217

Published: Feb. 17, 2024

Language: Английский

Citations

1
Some mechanistic underpinnings of molecular adaptations of SARS-COV-2 spike protein by integrating candidate adaptive polymorphisms with protein dynamics DOI Creative Commons
Nicholas J. Ose, Paul Campitelli, Tushar Modi

et al.

eLife, Journal Year: 2023, Volume and Issue: 12

Published: Nov. 6, 2023

We integrate evolutionary predictions based on the neutral theory of molecular evolution with protein dynamics to generate mechanistic insight into adaptations SARS-COV-2 spike (S) protein. With this approach, we first identified candidate adaptive polymorphisms (CAPs) SARS-CoV-2 S and assessed impact these CAPs through analysis. Not only have found that frequently overlap well-known functional sites, but also, using several different dynamics-based metrics, reveal critical allosteric interplay between binding sites human ACE2 (hACE2) interact far differently hACE2 site residues in open conformation compared closed form. In particular, CAP control state, suggesting an binding. also explored characteristic mutations strains find dynamic hallmarks potential effects future mutations. Our analyses Delta strain-specific variants non-additive (i.e., epistatic) interactions whereas less pathogenic Omicron mostly additive Finally, our analysis suggests novel observed strain epistatically help escape antibody

Language: Английский

Citations

2
Novel sofosbuvir derivatives against SARS-CoV-2 RNA-dependent RNA polymerase: an in silico perspective DOI Creative Commons

Abdulwahed Alrehaily,

Abdo A. Elfiky, Ibrahim M. Ibrahim

et al.

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: Dec. 27, 2023

Abstract The human coronavirus, SARS-CoV-2, had a negative impact on both the economy and health, emerging resistant variants are an ongoing threat. One essential protein to target prevent virus replication is viral RNA-dependent RNA polymerase (RdRp). Sofosbuvir, uridine nucleotide analog that potently inhibits polymerase, has been found help treat SARS-CoV-2 patients. This work combines molecular docking dynamics simulation (MDS) test 14 sofosbuvir-based modifications against RdRp. results reveal comparable (slightly better) average binding affinity of five (compounds 3 , 4 11 12 ) parent molecule, sofosbuvir. Compounds show best affinities RdRp (− 16.28 ± 5.69 − 16.25 5.78 kcal/mol energy compared 16.20 6.35 for sofosbuvir) calculated by Molecular Mechanics Generalized Born Surface Area (MM-GBSA) after MDS. present study proposes compounds as potential blockers, although this yet be proven experimentally.

Language: Английский

Citations

2
Some mechanistic underpinnings of molecular adaptations of SARS-COV-2 spike protein by integrating candidate adaptive polymorphisms with protein dynamics DOI Open Access
Nicholas J. Ose, Paul Campitelli, Tushar Modi

et al.

Published: April 3, 2024

We integrate evolutionary predictions based on the neutral theory of molecular evolution with protein dynamics to generate mechanistic insight into adaptations SARS-COV-2 Spike (S) protein. With this approach, we first identified Candidate Adaptive Polymorphisms (CAPs) SARS-CoV-2 and assessed impact these CAPs through analysis. Not only have found that frequently overlap well-known functional sites, but also, using several different dynamics-based metrics, reveal critical allosteric interplay between S binding sites human ACE2 (hACE2) interact far differently hACE2 site residues in open conformation compared closed form. In particular, CAP control state, suggesting an binding. also explored characteristic mutations strains find dynamic hallmarks potential effects future mutations. Our analyses Delta strain-specific variants non-additive (i.e., epistatic) interactions whereas less pathogenic Omicron mostly additive Finally, our analysis suggests novel observed strain epistatically help escape antibody

Language: Английский

Citations

0