and * represent mutant and crucial interactional residues, respectively. To compare the binding properties of SARS-CoV and SARS-CoV-2 RBDs to ACE2 at different temperatures, molecular dynamics (MD) simulations, analyses on structural stability, binding affinity and binding mechanisms were integrated into the current work (Figure 2). RBDs and ACE2. Finally, the hotspot residues facilitating the binding of SARS-CoV and SARS-CoV-2 RBDs to ACE2, the key differential residues contributing to the difference in binding and the interaction mechanism of differential residues that exist at all investigated temperatures were analyzed and compared in depth. The current work would provide a molecular basis for better understanding of the high infectiousness of SARS-CoV-2 and offer better theoretical guidance for the design of inhibitors targeting infectious diseases caused by SARS-CoV-2. simulation. The corresponding structures of SARS-CoV and SARS-CoV-2 RBDCACE2 complexes, and the superimposed structures of RBDs of SARS-CoV and SARS-CoV-2 (Figure 1A) are generated via PyMOL software (http://www.pymol.org). Notably, there are three disulfide bonds (SSBs) (C323CC348, C366CC419 and C467CC474) in the SARS-CoV RBD and four SSBs (C336CC361, C379CC432, C391CC525 and C480CC488) in the SARS-CoV-2 RBD, respectively, and these SSBs may partially contribute to the stabilization of S protein due to their important roles in maintaining the structural stability of proteins [29C31]. Structurally, the RBD of SARS-CoV/SARS-CoV-2 can be divided into alpha-Amyloid Precursor Protein Modulator two parts: the core region, which includes five sheets (1, 2, 3, 4 and 7), and the RBM, comprising residues N424CY494/S438CQ506. According to previous studies [32C35], the mutant residues may be responsible for the structural and interactional differences of the receptor and ligand. For a more intuitive demonstration of the differences in amino acid sequences between SARS-CoV and SARS-CoV-2 RBDs, sequence alignment was performed for the RBDs using MEGA software, and their sequence similarity is 72.38% (Figure 1B). In Figure 1B, mutant residues are marked in green, whereas key interactional residues are highlighted in blue according to the 2019 Novel Coronavirus Resource (2019nCoVR) provided by the China National Center for Bioinformation [36]. However, the difference in dynamic characteristics induced by the mutation of residues in SARS-CoV requires further in-depth analyses. Open in a separate window Figure 1 Crystal structures of proteins acquired from the RCSB PDB and sequence alignment. (A) Structures of SARS-CoV and SARS-CoV-2 RBDCACE2 complexes. The RBDs are shown in cartoon modes, whereas ACE2 is shown in surface style. The disulfide bonds and RBM are highlighted in cyan and pink in SARS-CoV RBD and blue and yellow in SARS-CoV-2 RBD, respectively. (B) Sequence alignment of SARS-CoV and SARS-CoV-2 RBDs. and * represent mutant and key interactional residues, respectively. To compare the binding properties of SARS-CoV and SARS-CoV-2 RBDs to ACE2 at different temperatures, molecular dynamics (MD) simulations, analyses on structural stability, binding affinity and binding mechanisms were integrated into the current work (Figure 2). First, all-atoms MD simulations were performed at five selected temperatures (200, 250, 273, 300 and 350?K) using Amber software [37]. Second, root-mean-square fluctuations (RMSFs) and principal component (PC) analyses were carried out to reveal the differences in structural stability between SARS-CoV and SARS-CoV-2 RBDs during MD simulations. Third, molecular mechanics PoissonCBoltzmann surface area (MM-PBSA) and solvated interaction energy (SIE) methods were combined to calculate the binding affinity of SARS-CoV and SARS-CoV-2 RBDs to ACE2 and to determine the major influential factor of their binding differences [38, 39]. Finally, the residue-based free energy decomposition method, hierarchical clustering (HC) and hydrogen-binding analyses were combined to probe the hotspot residues, key differential residues with significant contributions to the binding differences of the SARS-CoV/SARS-CoV-2 RBD to ACE2 and the interaction mechanism of the key differential residues existing at all studied temperatures. Understanding the atomic-level differences in structural stability of SARS-CoV/SARS-CoV-2 RBD and their binding abilities to ACE2 at different temperatures not only provides great potential for revealing the transmission mechanisms and designing potential drugs against SARS-CoV and SARS-CoV-2, but also offers better theoretical guidance for further experimental studies. Open in a separate window Figure 2 Flow chart for comparing the binding characteristics of SARS-CoV and SARS-CoV-2 RBDs to ACE2 at different temperatures. Materials and methods Preparation of systems The initial coordinates of the complexes under study were obtained from the PDB,.SynBio Research Platform, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China. Funding National Key Study and Development System of China [grant number 2018YFA0903700]; National Natural Science Basis of China [grant figures 21621004, 31571358, 91746119].. SARS-CoV-2 RBD was stronger than that to the SARS-CoV RBD at five temps, and the main reason for advertising such binding variations is definitely electrostatic and polar relationships between RBDs and ACE2. Finally, the hotspot residues facilitating the binding of SARS-CoV and SARS-CoV-2 RBDs to ACE2, the key differential residues contributing to the difference in binding and the connection mechanism of differential residues that exist at all investigated temps were analyzed and compared in depth. The current work would provide a molecular basis for better understanding of the high infectiousness of SARS-CoV-2 and offer better theoretical guidance for the design of inhibitors focusing on infectious diseases caused by SARS-CoV-2. simulation. The related constructions of SARS-CoV and SARS-CoV-2 RBDCACE2 complexes, and the superimposed constructions of RBDs of SARS-CoV and SARS-CoV-2 (Number 1A) are generated via PyMOL software (http://www.pymol.org). Notably, you will find three disulfide bonds (SSBs) (C323CC348, C366CC419 and C467CC474) in the SARS-CoV RBD and four SSBs (C336CC361, C379CC432, C391CC525 and C480CC488) in the SARS-CoV-2 RBD, respectively, and these SSBs may partially contribute to the stabilization of S protein because of the important functions in keeping the structural stability of proteins [29C31]. Structurally, the RBD of SARS-CoV/SARS-CoV-2 can be divided into two parts: the core region, which includes five linens (1, 2, Rabbit Polyclonal to GANP 3, 4 and 7), and alpha-Amyloid Precursor Protein Modulator the RBM, comprising residues N424CY494/S438CQ506. Relating to previous studies [32C35], the mutant residues may be responsible for the structural and interactional variations of the receptor and ligand. For a more intuitive demonstration of the variations in amino acid sequences between SARS-CoV and SARS-CoV-2 RBDs, sequence positioning was performed for the RBDs using MEGA software, and their sequence similarity is definitely 72.38% (Figure 1B). In Number 1B, mutant residues are designated in green, whereas key interactional residues are highlighted in blue according to the 2019 Novel Coronavirus Source (2019nCoVR) provided by the China National Center for Bioinformation [36]. However, the difference in dynamic characteristics induced from the mutation of residues in SARS-CoV requires further in-depth analyses. Open in a separate window Number 1 Crystal constructions of proteins acquired from your RCSB PDB and sequence alignment. (A) Constructions of SARS-CoV and SARS-CoV-2 RBDCACE2 complexes. The RBDs are demonstrated in cartoon modes, whereas ACE2 is definitely shown in surface style. The disulfide bonds and RBM are highlighted in cyan and pink in SARS-CoV RBD and blue and yellow in SARS-CoV-2 RBD, respectively. (B) Sequence positioning of SARS-CoV and SARS-CoV-2 RBDs. and * represent mutant and important interactional residues, respectively. To compare the binding properties of SARS-CoV and SARS-CoV-2 RBDs to ACE2 alpha-Amyloid Precursor Protein Modulator at different temps, molecular dynamics (MD) simulations, analyses on structural stability, binding affinity and binding mechanisms were integrated into the current work (Number 2). First, all-atoms MD simulations were performed at five selected temps (200, 250, 273, 300 and 350?K) using Amber software [37]. Second, root-mean-square fluctuations (RMSFs) and principal component (Personal computer) analyses were carried out to reveal the variations in structural stability between SARS-CoV and SARS-CoV-2 RBDs during MD simulations. Third, molecular mechanics PoissonCBoltzmann surface area (MM-PBSA) and solvated connection energy (SIE) methods were combined to calculate the binding affinity of SARS-CoV and SARS-CoV-2 RBDs to ACE2 and to determine alpha-Amyloid Precursor Protein Modulator the major influential element of their binding variations [38, 39]. Finally, the residue-based free energy decomposition method, hierarchical clustering (HC) and hydrogen-binding analyses were combined to probe the hotspot residues, important differential residues with significant contributions to the binding variations of the SARS-CoV/SARS-CoV-2 RBD to ACE2 and the connection mechanism of the key differential residues existing whatsoever studied temps. Understanding the atomic-level variations in structural stability of SARS-CoV/SARS-CoV-2 RBD and their binding capabilities to ACE2 at different temps not only provides great potential for revealing the transmission mechanisms and developing potential medicines against SARS-CoV and SARS-CoV-2, but also offers better theoretical guidance for further experimental studies. Open in a separate window Number 2 Flow chart for comparing the binding characteristics of SARS-CoV and SARS-CoV-2 RBDs to ACE2 at different temps. Materials and methods Preparation of systems The initial coordinates of the complexes under study were from the PDB, with PDB IDs 2AJF and 6M0J related to the SARS-CoV and SARS-CoV-2 RBDCACE2 complexes, respectively [25, 40]. Once the crystal structure of each system had been acquired, the preparation of the systems was carried out as follows: (a) product of the missing residues (D376-N381) in the SARS-CoV RBD by an online Modloop server [41]; (b) alternative of all CYSs involved in the formation of SSBs in Number 1 with CYXs to avoid adding hydrogen to the.
and * represent mutant and crucial interactional residues, respectively
- Post author:groundwater2011
- Post published:January 3, 2023
- Post category:Mitogen-Activated Protein Kinase