PMID- 35328828
OWN - NLM
STAT- MEDLINE
DCOM- 20220408
LR  - 20231103
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 23
IP  - 6
DP  - 2022 Mar 21
TI  - Improved Binding Affinity of Omicron's Spike Protein for the Human 
      Angiotensin-Converting Enzyme 2 Receptor Is the Key behind Its Increased 
      Virulence.
LID - 10.3390/ijms23063409 [doi]
LID - 3409
AB  - The new variant of severe acute respiratory syndrome coronavirus type 2 
      (SARS-CoV-2), Omicron, has been quickly spreading in many countries worldwide. 
      Compared to the original virus, Omicron is characterized by several mutations in 
      its genomic region, including the spike protein's receptor-binding domain (RBD). 
      We have computationally investigated the interaction between the RBD of both the 
      wild type and Omicron variant of SARS-CoV-2 with the human angiotensin-converting 
      enzyme 2 (hACE2) receptor using molecular dynamics and molecular 
      mechanics-generalized Born surface area (MM-GBSA)-based binding free energy 
      calculations. The mode of the interaction between Omicron's RBD with the hACE2 
      receptor is similar to the original SARS-CoV-2 RBD except for a few key 
      differences. The binding free energy difference shows that the spike protein of 
      Omicron has an increased affinity for the hACE2 receptor. The mutated residues in 
      the RBD showed strong interactions with a few amino acid residues of hACE2. More 
      specifically, strong electrostatic interactions (salt bridges) and hydrogen 
      bonding were observed between R493 and R498 residues of the Omicron RBD with 
      D30/E35 and D38 residues of the hACE2, respectively. Other mutated amino acids in 
      the Omicron RBD, e.g., S496 and H505, also exhibited hydrogen bonding with the 
      hACE2 receptor. A pi-stacking interaction was also observed between tyrosine 
      residues (RBD-Tyr501: hACE2-Tyr41) in the complex, which contributes majorly to 
      the binding free energies and suggests that this is one of the key interactions 
      stabilizing the formation of the complex. The resulting structural insights into 
      the RBD:hACE2 complex, the binding mode information within it, and residue-wise 
      contributions to the free energy provide insight into the increased 
      transmissibility of Omicron and pave the way to design and optimize novel 
      antiviral agents.
FAU - Kumar, Rajender
AU  - Kumar R
AD  - Division of Glycoscience, Department of Chemistry, School of Engineering Sciences 
      in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, 
      AlbaNova University Center, 106 91 Stockholm, Sweden.
FAU - Murugan, Natarajan Arul
AU  - Murugan NA
AUID- ORCID: 0000-0003-0185-5724
AD  - Department of Computer Science, School of Electrical Engineering and Computer 
      Science, KTH Royal Institute of Technology, 100 44 Stockholm, Sweden.
FAU - Srivastava, Vaibhav
AU  - Srivastava V
AUID- ORCID: 0000-0003-1877-4154
AD  - Division of Glycoscience, Department of Chemistry, School of Engineering Sciences 
      in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, 
      AlbaNova University Center, 106 91 Stockholm, Sweden.
LA  - eng
PT  - Journal Article
DEP - 20220321
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Spike Glycoprotein, Coronavirus)
RN  - 0 (spike protein, SARS-CoV-2)
RN  - EC 3.4.17.23 (ACE2 protein, human)
RN  - EC 3.4.17.23 (Angiotensin-Converting Enzyme 2)
RN  - SARS-CoV-2 variants
SB  - IM
MH  - Angiotensin-Converting Enzyme 2
MH  - *COVID-19
MH  - Humans
MH  - Protein Binding
MH  - SARS-CoV-2
MH  - *Spike Glycoprotein, Coronavirus/metabolism
MH  - Virulence
PMC - PMC8955673
OTO - NOTNLM
OT  - Omicron
OT  - human angiotensin-converting enzyme 2 (hACE2)
OT  - molecular dynamics simulation
OT  - molecular mechanics-generalized Born surface area (MM-GBSA)
OT  - receptor-binding domain (RBD)
OT  - receptor-binding motif (RBM)
OT  - severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)
COIS- The authors declare no conflict of interest.
EDAT- 2022/03/26 06:00
MHDA- 2022/04/09 06:00
PMCR- 2022/03/21
CRDT- 2022/03/25 01:08
PHST- 2021/12/26 00:00 [received]
PHST- 2022/01/24 00:00 [revised]
PHST- 2022/03/14 00:00 [accepted]
PHST- 2022/03/25 01:08 [entrez]
PHST- 2022/03/26 06:00 [pubmed]
PHST- 2022/04/09 06:00 [medline]
PHST- 2022/03/21 00:00 [pmc-release]
AID - ijms23063409 [pii]
AID - ijms-23-03409 [pii]
AID - 10.3390/ijms23063409 [doi]
PST - epublish
SO  - Int J Mol Sci. 2022 Mar 21;23(6):3409. doi: 10.3390/ijms23063409.