Quantum Chemical Computation of Omicron Mutations Near Cleavage Sites of the Spike Protein
Abstract
:1. Introduction
2. Methods
2.1. Model Construction
2.2. Vienna Ab Initio Simulation Package (VASP)
2.3. Orthogonalized Linear Combination of Atomic Orbitals (OLCAO) Method
3. Results
3.1. Amino Acid—Amino Acid Bond Pair (AABP) Unit
- (1)
- The largest total AABP is from site 796, close to cleavage site S2′, with only two NL–AAs. D796Y mutation reduces AABP slightly, but it increases size, surface exposure, and positive charge. The largest NN–AABP is from the same site 796 with only two NL–AAs. This confirms that NN–AA is the dominant interaction, as evidenced by the primary sequence of the S-protein.
- (2)
- (3)
- The 954 site has the largest NL–AABP contribution among all 10 mutations. It is part of the HR1 domain, as are the other two sites, 969 and 981, which have low NL–AABPs. These three Omicron mutations have slightly different interatomic interactions than their WT counterparts, while their size, shape, and PC*s are all changed. We speculate that these mutations may play a role in the binding of HR1 and HR2 domains to enhance the formation of six-helix-bundle (6-HB), which brings the viral lipid and the host lipid membranes close together, resulting in membrane fusion and the initiation of infection [40]. Here, it should be mentioned that the HR1-CH model alone is insufficient to assess this binding process. All atoms of the post-fusion S-protein must be included, which is currently impossible to do in a single ab initio calculation.
- (4)
- The smallest NL–AABP is from site 614 in group A ahead of the S1/S2 cleavage site. D614G mutation reduces the number of NL–AAs from 5 to 3 but results in a shift in charge distribution toward a more positively charged state, which could enhance the susceptibility of protease cleavage at the S1/S2 junction and/or promote the up conformation of the S-protein, as previously reported [41,42,43].
- (5)
- The largest contribution from HB to total AABP is from site 954, while the smallest HB contribution is from sites 614 and 655. This attests to the importance of the contribution of HB to the overall bonding network.
- (6)
- The role of the PC* distributions is obvious from five mutations, D614G, N679K, P681H, D796Y, and N969K. They exhibit a significantly changed, more positive, PC*. Importantly, the mutation at the 681 site, which is adjacent to the furin cleavage site, has been reported to play a significant function in the cleavage process [10,11,20,44]. Increasing the positive charge of P681H is necessary for the host furin-like proteases to cleave the S-protein [11]. Additionally, the N679K mutation is also located in the furin cleavage region and has been reported to increase the furin-mediated cleavage of Omicron [45]. However, some investigations have indicated that these N679K and P681H mutations do not enhance the S-protein cleavage processing and may even be less efficient [12,46,47,48]. This suggests that additional mutations near the furin cleavage site may interfere with its cleavage.
3.2. Interatomic Bonding
3.3. Partial Charge
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Models | Total AABP | NN AABP | NL-AABP | AABP (HB) | # NL AAs | Vol (Å3) | Surface (Å2) | PC*(e−) |
---|---|---|---|---|---|---|---|---|
WT D614 | 0.917 | 0.912 | 0.005 | 0.040 | 5 | 745.2 | 644.6 | 0.055 |
OV G614 | 0.908 | 0.907 | 0.002 | 0.042 | 3 | 640.3 | 564.5 | 0.961 |
WT H655 | 0.976 | 0.968 | 0.007 | 0.032 | 5 | 909.3 | 727.8 | −0.827 |
OV Y655 | 0.971 | 0.965 | 0.006 | 0.032 | 5 | 944.5 | 745.3 | −0.782 |
WT N679 | 1.022 | 0.956 | 0.066 | 0.081 | 3 | 624.6 | 533.9 | 0.833 |
OV K679 | 1.011 | 0.963 | 0.048 | 0.072 | 4 | 807.4 | 657.4 | 1.766 |
WT P681 | 1.117 | 1.064 | 0.054 | 0.064 | 5 | 872.2 | 757.9 | 2.862 |
OV H681 | 1.032 | 0.984 | 0.048 | 0.068 | 5 | 933.9 | 832.1 | 3.881 |
WT N764 | 1.130 | 1.008 | 0.121 | 0.137 | 6 | 959.5 | 775.1 | 1.043 |
OV K764 | 1.118 | 1.019 | 0.100 | 0.118 | 8 | 1211 | 986.4 | 1.181 |
WT D796 | 1.175 | 1.124 | 0.052 | 0.066 | 2 | 527.3 | 476.6 | 0.043 |
OV Y796 | 1.051 | 1.000 | 0.051 | 0.070 | 2 | 599.4 | 519.3 | 1.040 |
WT N856 | 0.935 | 0.894 | 0.041 | 0.069 | 3 | 609.9 | 554.0 | 0.783 |
OV K856 | 0.937 | 0.902 | 0.036 | 0.065 | 6 | 1081.0 | 822.5 | 1.801 |
WT Q954 | 1.148 | 1.008 | 0.140 | 0.152 | 7 | 1063.0 | 822.3 | 0.028 |
OV H954 | 1.146 | 1.008 | 0.139 | 0.155 | 7 | 1077.0 | 813.9 | 0.000 |
WT N969 | 0.938 | 0.907 | 0.031 | 0.052 | 5 | 774.1 | 624.5 | 0.188 |
OV K969 | 0.946 | 0.913 | 0.033 | 0.053 | 6 | 893.1 | 675.4 | 0.829 |
WT L981 | 0.898 | 0.893 | 0.005 | 0.036 | 5 | 960.1 | 754.9 | 0.090 |
OV F981 | 0.917 | 0.888 | 0.029 | 0.059 | 4 | 811.7 | 677.4 | 0.184 |
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Adhikari, P.; Jawad, B.; Podgornik, R.; Ching, W.-Y. Quantum Chemical Computation of Omicron Mutations Near Cleavage Sites of the Spike Protein. Microorganisms 2022, 10, 1999. https://doi.org/10.3390/microorganisms10101999
Adhikari P, Jawad B, Podgornik R, Ching W-Y. Quantum Chemical Computation of Omicron Mutations Near Cleavage Sites of the Spike Protein. Microorganisms. 2022; 10(10):1999. https://doi.org/10.3390/microorganisms10101999
Chicago/Turabian StyleAdhikari, Puja, Bahaa Jawad, Rudolf Podgornik, and Wai-Yim Ching. 2022. "Quantum Chemical Computation of Omicron Mutations Near Cleavage Sites of the Spike Protein" Microorganisms 10, no. 10: 1999. https://doi.org/10.3390/microorganisms10101999