PMID- 37542610
OWN - NLM
STAT- MEDLINE
DCOM- 20230918
LR  - 20230922
IS  - 1573-4951 (Electronic)
IS  - 0920-654X (Linking)
VI  - 37
IP  - 11
DP  - 2023 Nov
TI  - Investigating the role of glycans in Omicron sub-lineages XBB.1.5 and XBB.1.16 
      binding to host receptor using molecular dynamics and binding free energy 
      calculations.
PG  - 551-563
LID - 10.1007/s10822-023-00526-0 [doi]
AB  - Omicron derived lineages viz. BA.2, BA.3, BA.4 BA.5, BF.7 and XBBs show 
      prominence with improved immune escape, transmissibility, infectivity, and 
      pathogenicity in general. Sub-variants, XBB.1.5 and XBB.1.16 have shown rapid 
      spread, with mutations embedded throughout the viral genome, including the spike 
      protein. Changing atomic landscapes in spike contributes significantly to 
      modulate host pathogen interactions and infections thereof. In the present work, 
      we computationally analyzed the binding affinities of spike receptor binding 
      domains (RBDs) of XBB.1.5 and XBB.1.16 towards human angiotensin-converting 
      enzyme 2 (hACE2) compared to Omicron. We have employed simulations and binding 
      energy estimation of molecular complexes of spike-hACE2 to assess the interplay 
      of interaction pattern and effect of mutations if any in the binding mode of the 
      RBDs of these novel mutants. We calculated the binding free energy (BFE) of the 
      RBD of the Omicron, XBB.1.5 and XBB.1.16 spike protein to hACE2. We showed that 
      XBB.1.5 and XBB.1.16 can bind to human cells more strongly than Omicron due to 
      the increased charge of the RBD, which enhances the electrostatic interactions 
      with negatively charged hACE2. The per-residue decompositions further show that 
      the Asp339His, Asp405Asn and Asn460Lys mutations in the XBBs RBD play a crucial 
      role in enhancing the electrostatic interactions, by acquiring positively charged 
      residues, thereby influencing the formation/loss of interfacial bonds and thus 
      strongly affecting the spike RBD-hACE2 binding affinity. Simulation results also 
      indicate less interference of heterogeneous glycans of XBB.1.5 spike RBD towards 
      binding to hACE2. Moreover, despite having less interaction at the three 
      interfacial contacts between XBB S RBD and hACE2 compared to Omicron, variants 
      XBB.1.5 and XBB.1.16 had higher total binding free energies (DeltaG(bind)) than 
      Omicron due to the contribution of non-interfacial residues to the free energy, 
      providing insight into the increased binding affinity of XBB1.5 and XBB.1.16. 
      Furthermore, the presence of large positively charged surface patches in the XBBs 
      act as drivers of electrostatic interactions, thus support the possibility of a 
      higher binding affinity to hACE2.
CI  - (c) 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.
FAU - Singh, Jaikee Kumar
AU  - Singh JK
AD  - Structural Biology & Bioinformatics Laboratory, Department of Biosciences, 
      Manipal University Jaipur, Dehmi Kalan, Off Jaipur-Ajmer Expressway, Jaipur, 
      Rajasthan, 303007, India.
FAU - Singh, Jai
AU  - Singh J
AD  - Structural Biology & Bioinformatics Laboratory, Department of Biosciences, 
      Manipal University Jaipur, Dehmi Kalan, Off Jaipur-Ajmer Expressway, Jaipur, 
      Rajasthan, 303007, India.
FAU - Srivastava, Sandeep Kumar
AU  - Srivastava SK
AD  - Structural Biology & Bioinformatics Laboratory, Department of Biosciences, 
      Manipal University Jaipur, Dehmi Kalan, Off Jaipur-Ajmer Expressway, Jaipur, 
      Rajasthan, 303007, India. sandeepkumar.srivastava@jaipur.manipal.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230805
PL  - Netherlands
TA  - J Comput Aided Mol Des
JT  - Journal of computer-aided molecular design
JID - 8710425
RN  - 0 (Spike Glycoprotein, Coronavirus)
RN  - 0 (Polysaccharides)
SB  - IM
MH  - Humans
MH  - *Molecular Dynamics Simulation
MH  - *Spike Glycoprotein, Coronavirus/genetics
MH  - Mutation
MH  - Polysaccharides
MH  - Software
MH  - Protein Binding
OTO - NOTNLM
OT  - Binding affinity
OT  - Glycans
OT  - MD simulation
OT  - MM-PBSA
OT  - XBB
EDAT- 2023/08/06 05:42
MHDA- 2023/09/18 12:44
CRDT- 2023/08/05 11:06
PHST- 2023/06/07 00:00 [received]
PHST- 2023/07/26 00:00 [accepted]
PHST- 2023/09/18 12:44 [medline]
PHST- 2023/08/06 05:42 [pubmed]
PHST- 2023/08/05 11:06 [entrez]
AID - 10.1007/s10822-023-00526-0 [pii]
AID - 10.1007/s10822-023-00526-0 [doi]
PST - ppublish
SO  - J Comput Aided Mol Des. 2023 Nov;37(11):551-563. doi: 10.1007/s10822-023-00526-0. 
      Epub 2023 Aug 5.