Recent mutations on the receptor binding domain (RBD) of the SARS-CoV-2’s spike protein have been... more Recent mutations on the receptor binding domain (RBD) of the SARS-CoV-2’s spike protein have been manifested as the major cause of the wide and rapid spread of the virus. Especially, the variant B.1.351 in South Africa with the hallmark of triple mutations (N501Y, K417N and E484K) is worrisome. Quickly after the outbreak of this new variant, several studies showed that both N501Y and E484K can enhance the binding between RBD and the human ACE2 receptor. However, the mutation K417N seems to be unfavorable because it removes one interfacial salt-bridge. So far, it is still not well understood why the K417N mutation is selected in the viral evolution. Here, we show that despite the loss in the binding affinity (1.48 kcal/mol) between RBD and ACE2 the K417N mutation abolishes a buried interfacial salt-bridge between RBD and the neutralizing antibody CB6 and thus substantially reduces their binding energy by 9.59 kcal/mol, facilitating the variants to efficiently elude CB6 (as well as ma...
Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic and there are currently no FDA ... more Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic and there are currently no FDA approved medicines for treatment or prevention. Inspired by promising outcomes for convalescent plasma treatment, developing antibody drugs (biologics) to block SARS-CoV-2 infection has been the focus of drug discovery, along with tremendous efforts in repurposing small-molecule drugs. In the last several months, experimentally, many human neutralizing monoclonal antibodies (mAbs) were successfully extracted from plasma of recovered COVID-19 patients. Currently, several mAbs targeting the SARS-CoV-2's spike protein (Spro) are in clinical trials. With known atomic structures of mAb-Spro complex, it becomes possible to in silico investigate the molecular mechanism of mAb's binding with Spro and design more potent mAbs through protein mutagenesis studies, complementary to existing experimental efforts. Leveraging superb computing power nowadays, we propose a fully automated in silic...
Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic with very limited specific trea... more Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic with very limited specific treatments. To fight COVID-19, various traditional antiviral medicines haveb been prescribed in China to infected patients with mild to moderate symptoms and received unexpected success in controlling the disease. However, the molecular mechanisms of how these herbal medicines interact with the virus have remained elusive. It is well known that the main protease (Mpro) of SARS-CoV-2 plays an important role in maturation of many viral proteins such as the RNA-dependent RNA polymerase. Here,we explore the underlying molecular mechanisms of the computationally determined top candidate–rutin, a key component in many traditional antiviral medicines such as Lianhuaqinwen and Shuanghuanlian, for inhibiting the viral target–Mpro. Using in silico methods (docking and molecular dynamics simulations), we revealed the dynamics and energetics of rutin when interacting with the Mpro of SARS-CoV-2, suggest...
Single-stranded DNA (ssDNA) molecules in solution typically form coiled structures, therefore str... more Single-stranded DNA (ssDNA) molecules in solution typically form coiled structures, therefore stretching ssDNA is extremely crucial before applying any nanotechnology for ssDNA analysis. Recent advances in material fabrication enable the deployment of nanochannels to manipulate, stretch, sort and map double-stranded DNA (dsDNA) molecules, however nanochannels fail to stretch ssDNA molecules due to the ultra-short persistence length and the potential nonspecific-interaction-induced clogging. Given the significance of ssDNA stretching in genome analysis, here we report an ssDNA stretching platform: two dimensional in-plane heterostructure comprising graphene and hexagonal boron nitride (h-BN), and show that ssDNA can be stretched on a h-BN nanostripe sandwiched between two adjacent graphene domains (“nanochannel”). We further show that with a biasing voltage the stretched ssDNA can be electrophoretically transported along the “nanochannel”, allowing easy controls/manipulations. When b...
Engineered nanomaterials have been increasingly utilized in industry for various consumer product... more Engineered nanomaterials have been increasingly utilized in industry for various consumer products, environmental treatments, energy storage, and biomedical applications. Meanwhile, it has been established that certain nanomaterials can be toxic to biological cells from extensive experimental and theoretical studies. Despite that the exact molecular mechanisms of this nanomaterial toxicity are still not well understood, it is ubiquitous that their interactions with cell membranes, through either endocytosis or penetration (and thus potential lysis), act as the first step toward the inflammation or even the death of a cell. To facilitate the study of nanomaterial-membrane interactions, here we demonstrate a nanopore-based single-molecule approach that can be applied to monitor a specific nanomaterial-membrane interaction in real time. Combined with molecular dynamics and experimental approaches, we show how an ionic current can be used to detect membrane damage by a graphene nanoshee...
Accurate and rapid detection of single-nucleotide polymorphism (SNP) in pathogenic mutants is cru... more Accurate and rapid detection of single-nucleotide polymorphism (SNP) in pathogenic mutants is crucial for food safety regulation, disease diagnostics and many other fields. Current detection methods involve laborious sample preparations and expensive characterizations. Here, we investigated a nanopore-based single-molecule approach, facilitated by the locked nucleic acid (LNA) technique, to accurately determine SNPs for detection of Shiga toxin producing Escherichia coli (STEC) O157:H7 serotype, and cancer-derived EGFR L858R and KRAS G12D driver mutations. Remarkably, unlike traditional LNA applications that need incorporation and optimization of multiple LNA nucleotides, we found that in the nanopore system, a single LNA introduced in the probe is sufficient to enhance the SNP discrimination capability by over 10-fold, allowing accurate detection of the pathogenic mutant DNA mixed in a large amount of the wild-type DNA. The mechanistic study suggests that such a significant improve...
Examining interactions between nanomaterials and cell membranes can expose underlying mechanisms ... more Examining interactions between nanomaterials and cell membranes can expose underlying mechanisms of nanomaterial cytotoxicity and guide the design of safer nanomedical technologies. Recently, graphene has been shown to exhibit potential toxicity to cells; however, the molecular processes driving its lethal properties have yet to be fully characterized. We here demonstrate that graphene nanosheets (both pristine and oxidized) can produce holes (pores) in the membranes of A549 and Raw264.7 cells, substantially reducing cell viability. Electron micrographs offer clear evidence of pores created on cell membranes. Our molecular dynamics simulations reveal that multiple graphene nanosheets can cooperate to extract large numbers of phospholipids from the membrane bilayer. Strong dispersion interactions between graphene and lipid-tail carbons result in greatly depleted lipid density within confined regions of the membrane, ultimately leading to the formation of water-permeable pores. This c...
Engineered nanomaterials promise to transform medicine at the bio-nano interface. However, it is ... more Engineered nanomaterials promise to transform medicine at the bio-nano interface. However, it is important to elucidate how synthetic nanomaterials interact with critical biological systems before such products can be safely utilized in humans. Past evidence suggests that polyethylene glycol-functionalized (PEGylated) nanomaterials are largely biocompatible and elicit less dramatic immune responses than their pristine counterparts. We here report results that contradict these findings. We find that PEGylated graphene oxide nanosheets (nGO-PEGs) stimulate potent cytokine responses in peritoneal macrophages, despite not being internalized. Atomistic molecular dynamics simulations support a mechanism by which nGO-PEGs preferentially adsorb onto and/or partially insert into cell membranes, thereby amplifying interactions with stimulatory surface receptors. Further experiments demonstrate that nGO-PEG indeed provokes cytokine secretion by enhancing integrin β8-related signalling pathways...
An assortment of biological processes, like protein degradation and the transport of proteins acr... more An assortment of biological processes, like protein degradation and the transport of proteins across membranes, depend on protein unfolding events mediated by nanopore interfaces. In this work, we exploit fully atomistic simulations of an artificial, CNT-based nanopore to investigate the nature of ubiquitin unfolding. With one end of the protein subjected to an external force, we observe non-canonical unfolding behaviour as ubiquitin is pulled through the pore opening. Secondary structural elements are sequentially detached from the protein and threaded into the nanotube, interestingly, the remaining part maintains native-like characteristics. The constraints of the nanopore interface thus facilitate the formation of stable "unfoldon" motifs above the nanotube aperture that can exist in the absence of specific native contacts with the other secondary structure. Destruction of these unfoldons gives rise to distinct force peaks in our simulations, providing us with a sensiti...
Ultra-thin nanopores have become promising biological sensors because of their outstanding signal... more Ultra-thin nanopores have become promising biological sensors because of their outstanding signal-to-noise ratio and spatial resolution. Here, we show that boron nitride (BN), which is a new two-dimensional (2D) material similar to graphene, could be utilized for making a nanopore with an atomic thickness. Using an all-atom molecular dynamics simulation, we investigated the dynamics of DNA translocation through the BN nanopore. The results of our simulations demonstrated that it is possible to detect different double-stranded DNA (dsDNA) sequences from the recording of ionic currents through the pore during the DNA translocation. Surprisingly, opposite to results for a graphene nanopore, we found the calculated blockage current for poly(A-T)40 in a BN nanopore to be less than that for poly(G-C)40. Also in contrast with the case of graphene nanopores, dsDNA models moved smoothly and in an unimpeded manner through the BN nanopores in the simulations, suggesting a potential advantage f...
Counterion-induced inversion of the DNA charge was characterized through extensive molecular dyna... more Counterion-induced inversion of the DNA charge was characterized through extensive molecular dynamics simulations. We observed reversal of the DNA motion in an external electric field upon increasing the concentration of trivalent or quadrivalent counterions. In the case of a divalent electrolyte, inversion of the DNA's electric charge was observed at high concentrations of the electrolyte but not reversal of the DNA' electrophoretic motion. We demonstrate that inversion of the DNA's electrophoretic mobility results from a complex interplay of electrostatics and hydrodynamics.
Physical review. E, Statistical, nonlinear, and soft matter physics, 2006
Atomistic simulations are used to test the equations of continuum contact mechanics in nanometer ... more Atomistic simulations are used to test the equations of continuum contact mechanics in nanometer scale contacts. Nominally spherical tips, made by bending crystals or cutting crystalline or amorphous solids, are pressed into a flat, elastic substrate. The normal displacement, contact radius, stress distribution, friction, and lateral stiffness are examined as a function of load and adhesion. The atomic scale roughness present on any tip made of discrete atoms is shown to have profound effects on the results. Contact areas, local stresses, and the work of adhesion change by factors of 2 to 4, and the friction and lateral stiffness vary by orders of magnitude. The microscopic factors responsible for these changes are discussed. The results are also used to test methods for analyzing experimental data with continuum theory to determine information, such as contact area, that cannot be measured directly in nanometer scale contacts. Even when the data appear to be fit by continuum theory...
Channels formed by membrane proteins regulate the transport of water, ions or nutrients that are ... more Channels formed by membrane proteins regulate the transport of water, ions or nutrients that are essential to cells' metabolism. Recent advances in nanotechnology allow us to fabricate solid-state nanopores for transporting and analyzing biomolecules. However, uncontrollable surface properties of a fabricated nanopore cause irregular transport of biomolecules, limiting potential biomimetic applications. Here we show that a nanopore functionalized with a self-assembled monolayer (SAM) can potentially regulate the transport of a DNA molecule by changing functional groups of the SAM. We found that an enhanced interaction between DNA and a SAM-coated nanopore can slow down the translocation speed of DNA molecules and increase the DNA capture-rate. Our results demonstrate that the transport of DNA molecules inside nanopores could be modulated by coating a SAM on the pore surface. Our method to control the DNA motion inside a nanopore may find its applications in nanopore-based DNA se...
Both cytosine-Ag-cytosine interactions and cytosine modifications in a DNA duplex have attracted ... more Both cytosine-Ag-cytosine interactions and cytosine modifications in a DNA duplex have attracted great interest for research. Cytosine (C) modifications such as methylcytosine (mC) and hydroxymethylcytosine (hmC) are associated with tumorigenesis. However, a method for directly discriminating C, mC and hmC bases without labeling, modification and amplification is still missing. Additionally, the nature of coordination of Ag+ with cytosine-cytosine (C-C) mismatches is not clearly understood. Utilizing the alpha-hemolysin nanopore, we show that in the presence of Ag+, duplex stability is most increased for the cytosine-cytosine (C-C) pair, followed by the cytosine-methylcytosine (C-mC) pair and the cytosine-hydroxymethylcytosine (C-hmC) pair, which has no observable Ag+ induced stabilization. Molecular dynamics simulations reveal that the hydrogen-bond-mediated paring of a C-C mismatch results in a binding site for Ag+. Cytosine modifications (such as mC and hmC) disrupted the hydroge...
Recent mutations on the receptor binding domain (RBD) of the SARS-CoV-2’s spike protein have been... more Recent mutations on the receptor binding domain (RBD) of the SARS-CoV-2’s spike protein have been manifested as the major cause of the wide and rapid spread of the virus. Especially, the variant B.1.351 in South Africa with the hallmark of triple mutations (N501Y, K417N and E484K) is worrisome. Quickly after the outbreak of this new variant, several studies showed that both N501Y and E484K can enhance the binding between RBD and the human ACE2 receptor. However, the mutation K417N seems to be unfavorable because it removes one interfacial salt-bridge. So far, it is still not well understood why the K417N mutation is selected in the viral evolution. Here, we show that despite the loss in the binding affinity (1.48 kcal/mol) between RBD and ACE2 the K417N mutation abolishes a buried interfacial salt-bridge between RBD and the neutralizing antibody CB6 and thus substantially reduces their binding energy by 9.59 kcal/mol, facilitating the variants to efficiently elude CB6 (as well as ma...
Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic and there are currently no FDA ... more Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic and there are currently no FDA approved medicines for treatment or prevention. Inspired by promising outcomes for convalescent plasma treatment, developing antibody drugs (biologics) to block SARS-CoV-2 infection has been the focus of drug discovery, along with tremendous efforts in repurposing small-molecule drugs. In the last several months, experimentally, many human neutralizing monoclonal antibodies (mAbs) were successfully extracted from plasma of recovered COVID-19 patients. Currently, several mAbs targeting the SARS-CoV-2's spike protein (Spro) are in clinical trials. With known atomic structures of mAb-Spro complex, it becomes possible to in silico investigate the molecular mechanism of mAb's binding with Spro and design more potent mAbs through protein mutagenesis studies, complementary to existing experimental efforts. Leveraging superb computing power nowadays, we propose a fully automated in silic...
Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic with very limited specific trea... more Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic with very limited specific treatments. To fight COVID-19, various traditional antiviral medicines haveb been prescribed in China to infected patients with mild to moderate symptoms and received unexpected success in controlling the disease. However, the molecular mechanisms of how these herbal medicines interact with the virus have remained elusive. It is well known that the main protease (Mpro) of SARS-CoV-2 plays an important role in maturation of many viral proteins such as the RNA-dependent RNA polymerase. Here,we explore the underlying molecular mechanisms of the computationally determined top candidate–rutin, a key component in many traditional antiviral medicines such as Lianhuaqinwen and Shuanghuanlian, for inhibiting the viral target–Mpro. Using in silico methods (docking and molecular dynamics simulations), we revealed the dynamics and energetics of rutin when interacting with the Mpro of SARS-CoV-2, suggest...
Single-stranded DNA (ssDNA) molecules in solution typically form coiled structures, therefore str... more Single-stranded DNA (ssDNA) molecules in solution typically form coiled structures, therefore stretching ssDNA is extremely crucial before applying any nanotechnology for ssDNA analysis. Recent advances in material fabrication enable the deployment of nanochannels to manipulate, stretch, sort and map double-stranded DNA (dsDNA) molecules, however nanochannels fail to stretch ssDNA molecules due to the ultra-short persistence length and the potential nonspecific-interaction-induced clogging. Given the significance of ssDNA stretching in genome analysis, here we report an ssDNA stretching platform: two dimensional in-plane heterostructure comprising graphene and hexagonal boron nitride (h-BN), and show that ssDNA can be stretched on a h-BN nanostripe sandwiched between two adjacent graphene domains (“nanochannel”). We further show that with a biasing voltage the stretched ssDNA can be electrophoretically transported along the “nanochannel”, allowing easy controls/manipulations. When b...
Engineered nanomaterials have been increasingly utilized in industry for various consumer product... more Engineered nanomaterials have been increasingly utilized in industry for various consumer products, environmental treatments, energy storage, and biomedical applications. Meanwhile, it has been established that certain nanomaterials can be toxic to biological cells from extensive experimental and theoretical studies. Despite that the exact molecular mechanisms of this nanomaterial toxicity are still not well understood, it is ubiquitous that their interactions with cell membranes, through either endocytosis or penetration (and thus potential lysis), act as the first step toward the inflammation or even the death of a cell. To facilitate the study of nanomaterial-membrane interactions, here we demonstrate a nanopore-based single-molecule approach that can be applied to monitor a specific nanomaterial-membrane interaction in real time. Combined with molecular dynamics and experimental approaches, we show how an ionic current can be used to detect membrane damage by a graphene nanoshee...
Accurate and rapid detection of single-nucleotide polymorphism (SNP) in pathogenic mutants is cru... more Accurate and rapid detection of single-nucleotide polymorphism (SNP) in pathogenic mutants is crucial for food safety regulation, disease diagnostics and many other fields. Current detection methods involve laborious sample preparations and expensive characterizations. Here, we investigated a nanopore-based single-molecule approach, facilitated by the locked nucleic acid (LNA) technique, to accurately determine SNPs for detection of Shiga toxin producing Escherichia coli (STEC) O157:H7 serotype, and cancer-derived EGFR L858R and KRAS G12D driver mutations. Remarkably, unlike traditional LNA applications that need incorporation and optimization of multiple LNA nucleotides, we found that in the nanopore system, a single LNA introduced in the probe is sufficient to enhance the SNP discrimination capability by over 10-fold, allowing accurate detection of the pathogenic mutant DNA mixed in a large amount of the wild-type DNA. The mechanistic study suggests that such a significant improve...
Examining interactions between nanomaterials and cell membranes can expose underlying mechanisms ... more Examining interactions between nanomaterials and cell membranes can expose underlying mechanisms of nanomaterial cytotoxicity and guide the design of safer nanomedical technologies. Recently, graphene has been shown to exhibit potential toxicity to cells; however, the molecular processes driving its lethal properties have yet to be fully characterized. We here demonstrate that graphene nanosheets (both pristine and oxidized) can produce holes (pores) in the membranes of A549 and Raw264.7 cells, substantially reducing cell viability. Electron micrographs offer clear evidence of pores created on cell membranes. Our molecular dynamics simulations reveal that multiple graphene nanosheets can cooperate to extract large numbers of phospholipids from the membrane bilayer. Strong dispersion interactions between graphene and lipid-tail carbons result in greatly depleted lipid density within confined regions of the membrane, ultimately leading to the formation of water-permeable pores. This c...
Engineered nanomaterials promise to transform medicine at the bio-nano interface. However, it is ... more Engineered nanomaterials promise to transform medicine at the bio-nano interface. However, it is important to elucidate how synthetic nanomaterials interact with critical biological systems before such products can be safely utilized in humans. Past evidence suggests that polyethylene glycol-functionalized (PEGylated) nanomaterials are largely biocompatible and elicit less dramatic immune responses than their pristine counterparts. We here report results that contradict these findings. We find that PEGylated graphene oxide nanosheets (nGO-PEGs) stimulate potent cytokine responses in peritoneal macrophages, despite not being internalized. Atomistic molecular dynamics simulations support a mechanism by which nGO-PEGs preferentially adsorb onto and/or partially insert into cell membranes, thereby amplifying interactions with stimulatory surface receptors. Further experiments demonstrate that nGO-PEG indeed provokes cytokine secretion by enhancing integrin β8-related signalling pathways...
An assortment of biological processes, like protein degradation and the transport of proteins acr... more An assortment of biological processes, like protein degradation and the transport of proteins across membranes, depend on protein unfolding events mediated by nanopore interfaces. In this work, we exploit fully atomistic simulations of an artificial, CNT-based nanopore to investigate the nature of ubiquitin unfolding. With one end of the protein subjected to an external force, we observe non-canonical unfolding behaviour as ubiquitin is pulled through the pore opening. Secondary structural elements are sequentially detached from the protein and threaded into the nanotube, interestingly, the remaining part maintains native-like characteristics. The constraints of the nanopore interface thus facilitate the formation of stable "unfoldon" motifs above the nanotube aperture that can exist in the absence of specific native contacts with the other secondary structure. Destruction of these unfoldons gives rise to distinct force peaks in our simulations, providing us with a sensiti...
Ultra-thin nanopores have become promising biological sensors because of their outstanding signal... more Ultra-thin nanopores have become promising biological sensors because of their outstanding signal-to-noise ratio and spatial resolution. Here, we show that boron nitride (BN), which is a new two-dimensional (2D) material similar to graphene, could be utilized for making a nanopore with an atomic thickness. Using an all-atom molecular dynamics simulation, we investigated the dynamics of DNA translocation through the BN nanopore. The results of our simulations demonstrated that it is possible to detect different double-stranded DNA (dsDNA) sequences from the recording of ionic currents through the pore during the DNA translocation. Surprisingly, opposite to results for a graphene nanopore, we found the calculated blockage current for poly(A-T)40 in a BN nanopore to be less than that for poly(G-C)40. Also in contrast with the case of graphene nanopores, dsDNA models moved smoothly and in an unimpeded manner through the BN nanopores in the simulations, suggesting a potential advantage f...
Counterion-induced inversion of the DNA charge was characterized through extensive molecular dyna... more Counterion-induced inversion of the DNA charge was characterized through extensive molecular dynamics simulations. We observed reversal of the DNA motion in an external electric field upon increasing the concentration of trivalent or quadrivalent counterions. In the case of a divalent electrolyte, inversion of the DNA's electric charge was observed at high concentrations of the electrolyte but not reversal of the DNA' electrophoretic motion. We demonstrate that inversion of the DNA's electrophoretic mobility results from a complex interplay of electrostatics and hydrodynamics.
Physical review. E, Statistical, nonlinear, and soft matter physics, 2006
Atomistic simulations are used to test the equations of continuum contact mechanics in nanometer ... more Atomistic simulations are used to test the equations of continuum contact mechanics in nanometer scale contacts. Nominally spherical tips, made by bending crystals or cutting crystalline or amorphous solids, are pressed into a flat, elastic substrate. The normal displacement, contact radius, stress distribution, friction, and lateral stiffness are examined as a function of load and adhesion. The atomic scale roughness present on any tip made of discrete atoms is shown to have profound effects on the results. Contact areas, local stresses, and the work of adhesion change by factors of 2 to 4, and the friction and lateral stiffness vary by orders of magnitude. The microscopic factors responsible for these changes are discussed. The results are also used to test methods for analyzing experimental data with continuum theory to determine information, such as contact area, that cannot be measured directly in nanometer scale contacts. Even when the data appear to be fit by continuum theory...
Channels formed by membrane proteins regulate the transport of water, ions or nutrients that are ... more Channels formed by membrane proteins regulate the transport of water, ions or nutrients that are essential to cells' metabolism. Recent advances in nanotechnology allow us to fabricate solid-state nanopores for transporting and analyzing biomolecules. However, uncontrollable surface properties of a fabricated nanopore cause irregular transport of biomolecules, limiting potential biomimetic applications. Here we show that a nanopore functionalized with a self-assembled monolayer (SAM) can potentially regulate the transport of a DNA molecule by changing functional groups of the SAM. We found that an enhanced interaction between DNA and a SAM-coated nanopore can slow down the translocation speed of DNA molecules and increase the DNA capture-rate. Our results demonstrate that the transport of DNA molecules inside nanopores could be modulated by coating a SAM on the pore surface. Our method to control the DNA motion inside a nanopore may find its applications in nanopore-based DNA se...
Both cytosine-Ag-cytosine interactions and cytosine modifications in a DNA duplex have attracted ... more Both cytosine-Ag-cytosine interactions and cytosine modifications in a DNA duplex have attracted great interest for research. Cytosine (C) modifications such as methylcytosine (mC) and hydroxymethylcytosine (hmC) are associated with tumorigenesis. However, a method for directly discriminating C, mC and hmC bases without labeling, modification and amplification is still missing. Additionally, the nature of coordination of Ag+ with cytosine-cytosine (C-C) mismatches is not clearly understood. Utilizing the alpha-hemolysin nanopore, we show that in the presence of Ag+, duplex stability is most increased for the cytosine-cytosine (C-C) pair, followed by the cytosine-methylcytosine (C-mC) pair and the cytosine-hydroxymethylcytosine (C-hmC) pair, which has no observable Ag+ induced stabilization. Molecular dynamics simulations reveal that the hydrogen-bond-mediated paring of a C-C mismatch results in a binding site for Ag+. Cytosine modifications (such as mC and hmC) disrupted the hydroge...
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