Evaluation of Interactions between SARS-CoV-2 RBD and Full-Length ACE2 with Coarse-Grained Molecular Dynamics Simulations

Ma, Baocai; Zhang, Zuoheng; Li, Yan; Lin, Xubo; Gu, Ning

doi:10.1021/acs.jcim.1c01306

Cited by 10 publications

(9 citation statements)

References 31 publications

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“…The binding of RBD with human ACE2 has been studied in many recent studies through computational means. − Although these studies have greatly contributed to our understanding of the RBD-ACE2 binding process, many details of the molecular mechanism of the binding, the process of unbinding and associated free energy diagrams, and their variations with mutation still remain open. For example, while the experimental work of ref reported that the receptor binding domains of SARS-CoV-2 and SARS-CoV-1 bind with ACE2 with similar affinities, the biomechanical force measurements and computational studies of refs and − reported that SARS-CoV-2 binds with ACE2 with higher affinity than SARS-CoV-1.…”

Section: Introductionmentioning

confidence: 99%

All-Atom Simulations of Human ACE2-Spike Protein RBD Complexes for SARS-CoV-2 and Some of its Variants: Nature of Interactions and Free Energy Diagrams for Dissociation of the Protein Complexes

2022

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The spike protein of SARS-CoV-2 is known to interact with the human ACE2 protein via its receptor binding domain (RBD). We have investigated the molecular nature of this interprotein interaction and the associated free energy diagrams for the unbinding of the two proteins for SARS-CoV-2 and some of its known variants through all-atom simulations. The present work involves generation and analysis of 2.5 μs of unbiased and 4.2 μs of biased molecular dynamics trajectories in total for five explicitly solvated RBD-ACE2 systems at full atomic level. First, we have made a comparative analysis of the details of residue-wise specific interactions of the spike protein with ACE2 for SARS-CoV-1 and SARS-CoV-2. It is found that the average numbers of both direct interprotein and water-bridged hydrogen bonds between the RBD and ACE2 are higher for SARS-CoV-2 than SARS-CoV-1. These higher hydrogen bonded interactions are further aided by enhanced nonspecific electrostatic attractions between the two protein surfaces for SARS-CoV-2. The free energy calculations reveal that there is an increase in the free energy barrier by ∼1.5 kcal/mol for the unbinding of RBD from ACE2 for SARS-CoV-2 compared to that for SARS-CoV-1. Subsequently, we considered the RBDs of three variants of SARS-CoV-2, namely N501Y, E484Q/L452R, and N440K. The free energy barrier of protein unbinding for the N501Y variant is found to be ∼4 kcal/mol higher than the wild type SARS-CoV-2 which can be attributed to additional specific interactions involving Tyr501 of RBD and Lys353 and Tyr42 of ACE2 and also enhanced nonspecific electrostatic interaction between the protein surfaces. For the other two mutant variants of E484Q/L452R and N440K, the free energy barrier for protein unbinding increases by ∼2 and ∼1 kcal/mol, respectively, compared with the wild type SARS-CoV-2, which can be attributed to an increase in the number of interprotein hydrogen bonds for the former and also to enhanced positive electrostatic potential on the RBD surfaces for both of the variants. The successive breaking of interprotein hydrogen bonds along the free energy pathway of the unbinding process is also found out for all five systems studied here.

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Section: Introductionmentioning

confidence: 99%

All-Atom Simulations of Human ACE2-Spike Protein RBD Complexes for SARS-CoV-2 and Some of its Variants: Nature of Interactions and Free Energy Diagrams for Dissociation of the Protein Complexes

2022

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“…In the same year, Martini (v2.2) was used to study the SARS-Cov-2 virus. By exploiting the increased time and sizes scales inherent in CGMD, the entire viral envelope was able to be simulated. − These examples show the scale of simulations possible, which remain inaccessible to all-atom MD.…”

Section: Introductionmentioning

confidence: 99%

Short Peptide Self-Assembly in the Martini Coarse-Grain Force Field Family

2023

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Conspectus Pivotal to the success of any computational experiment is the ability to make reliable predictions about the system under study and the time required to yield these results. Biomolecular interactions is one area of research that sits in every camp of resolution vs the time required, from the quantum mechanical level to in vivo studies. At an approximate midpoint, there is coarse-grained molecular dynamics, for which the Martini force fields have become the most widely used, fast enough to simulate the entire membrane of a mitochondrion though lacking atom-specific precision. While many force fields have been parametrized to account for a specific system under study, the Martini force field has aimed at casting a wider net with more generalized bead types that have demonstrated suitability for broad use and reuse in applications from protein–graphene oxide coassembly to polysaccharides interactions. In this Account, the progressive (Martini versions 1 through 3) and peripheral (Sour Martini, constant pH, Martini Straight, Dry Martini, etc.) developmental trajectory of the Martini force field will be analyzed in terms of self-assembling systems with a focus on short (two to three amino acids) peptide self-assembly in aqueous environments. In particular, this will focus on the effects of the Martini solvent model and compare how changes in bead definitions and mapping have effects on different systems. Considerable effort in the development of Martini has been expended to reduce the “stickiness” of amino acids to better simulate proteins in bilayers. We have included in this Account a short study of dipeptide self-assembly in water, using all mainstream Martini force fields, to examine their ability to reproduce this behavior. The three most recently released versions of Martini and variations in their solvents are used to simulate in triplicate all 400 dipeptides of the 20 gene-encoded amino acids. The ability of the force fields to model the self-assembly of the dipeptides in aqueoues environments is determined by the measurement of the aggregation propensity, and additional descriptors are used to gain further insight into the dipeptide aggregates.

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“…Amitai 54 constructed a shape-based CG model for the SARS-CoV-2 S-protein and conducted the on-rate (targeting) analysis to predict important mutation sites in the S-protein. Gu and co-workers 55 used the MARTINI force field to simulate the binding form of SARS-CoV-2 RBD with ACE2, and they found that the plier structure at both ends of the RBD-ACE2 interface would benefit the interaction between the RBD and the full-length human ACE2. Tieleman and co-workers 56 constructed the MARTINI CG models for the intact envelopes of SARS-CoVs containing multiple S-proteins.…”

Section: Introductionmentioning

confidence: 99%

Effect of Disulfide Bridge on the Binding of SARS-CoV-2 Fusion Peptide to Cell Membrane: A Coarse-Grained Study

Shen

2022

ACS Omega

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In this paper, we present the parameterization of the CAVS coarse-grained (CG) force field for 20 amino acids, and our CG simulations show that the CAVS force field could accurately predict the amino acid tendency of the secondary structure. Then, we used the CAVS force field to investigate the binding of a severe acute respiratory syndrome-associated coronavirus fusion peptide (SARS-CoV-2 FP) to a phospholipid bilayer: a long FP (FP-L) containing 40 amino acids and a short FP (FP-S) containing 26 amino acids. Our CAVS CG simulations displayed that the binding affinity of the FP-L to the bilayer is higher than that of the FP-S. We found that the FP-L interacted more strongly with membrane cholesterol than the FP-S, which should be attributed to the stable helical structure of the FP-L at the C-terminus. In addition, we discovered that the FP-S had one major and two minor membrane-bound states, in agreement with previous all-atom molecular dynamics (MD) studies. However, we found that both the C-terminal and N-terminal amino acid residues of the FP-L can strongly interact with the bilayer membrane. Furthermore, we found that the disulfide bond formed between Cys840 and Cys851 stabilized the helices of the FP-L at the C-terminus, enhancing the interaction between the FP-L and the bilayer membrane. Our work indicates that the stable helical structure is crucial for binding the SARS-CoV-2 FP to cell membranes. In particular, the helical stability of FP should have a significant influence on the FP–membrane binding.

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Evaluation of Interactions between SARS-CoV-2 RBD and Full-Length ACE2 with Coarse-Grained Molecular Dynamics Simulations

Cited by 10 publications

References 31 publications

All-Atom Simulations of Human ACE2-Spike Protein RBD Complexes for SARS-CoV-2 and Some of its Variants: Nature of Interactions and Free Energy Diagrams for Dissociation of the Protein Complexes

All-Atom Simulations of Human ACE2-Spike Protein RBD Complexes for SARS-CoV-2 and Some of its Variants: Nature of Interactions and Free Energy Diagrams for Dissociation of the Protein Complexes

Short Peptide Self-Assembly in the Martini Coarse-Grain Force Field Family

Effect of Disulfide Bridge on the Binding of SARS-CoV-2 Fusion Peptide to Cell Membrane: A Coarse-Grained Study

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