Tiến Phan Huỳnh - Academia.edu (original) (raw)
Papers by Tiến Phan Huỳnh
Lecture Notes in Computer Science, 1990
We address the problem of building intelligent query systems to reason about linear arithmetic co... more We address the problem of building intelligent query systems to reason about linear arithmetic constraints. The central issue is the development of tools for testing solvability, for constraints representation, for incremental updates and for intelligent feedback. The ...
Lecture Notes in Computer Science, 1990
Only comparatively recently, Fourier solvability algorithm for linear constraints has been shown ... more Only comparatively recently, Fourier solvability algorithm for linear constraints has been shown to be of great theoretical interest in Linear Programming: the fundamental duality theorem and other major results are a direct consequence of it. We show here that Fourier ...
Annals of Mathematics and Artificial Intelligence, 1992
Projection of polyhedral sets is a fundamental operation in both geometry and symbolic computatio... more Projection of polyhedral sets is a fundamental operation in both geometry and symbolic computation. In most cases, however, it is not practically feasible to generate projections as the size of the output can be exponential in the size of the input. Even when the size of the ...
ACS Nano, 2015
While carbon-based nanomaterials such as graphene and carbon nanotubes (CNTs) have become popular... more While carbon-based nanomaterials such as graphene and carbon nanotubes (CNTs) have become popular in state-of-the-art nanotechnology, their biological safety and underlying molecular mechanism is still largely unknown. Experimental studies have been focused at the cellular level and revealed good correlations between cell's death and the application of CNTs or graphene. Using large-scale all-atom molecular dynamics simulations, we theoretically investigate the potential toxicity of graphene to a biological cell at molecular level. Simulation results show that the hydrophobic protein-protein interaction (or recognition) that is essential to biological functions can be interrupted by a graphene nanosheet. Due to the hydrophobic nature of graphene, it is energetically favorable for a graphene nanosheet to enter the hydrophobic interface of two contacting proteins, such as a dimer. The forced separation of two functional proteins can disrupt the cell's metabolism and even lead to the cell's mortality.
The Journal of Physical Chemistry Letters, 2015
Developing a low-cost and high-efficacy method to optimize prescreened or designed drug candidate... more Developing a low-cost and high-efficacy method to optimize prescreened or designed drug candidates will facilitate drug discovery and biomedical research in general. Current methods of drug screening usually involve tedious sample preparation and costly biological/chemical assays. Here, through all-atom molecular dynamics simulations, we propose a new drug optimization method, based on the nanopore force spectroscopy, to electrically detect the binding strength between a drug molecule and a target protein. Simulation results demonstrate that the drug-protein complex can be electrophoretically driven into a nanopore, which is followed by the rupture of the complex at a critical biasing voltage. The latter determines the binding strength of the tested drug molecule. It is expected that the application of this single-molecule technology could help to accelerate the drug discovery, particularly for processes of the narrow screening and further lead optimization.
Nanoscale, 2014
We investigate the possible ratcheting dynamics of double-stranded DNA (dsDNA) driven through a Y... more We investigate the possible ratcheting dynamics of double-stranded DNA (dsDNA) driven through a Yshaped carbon nanotube (Y-CNT) in a solid membrane, using all-atom molecular dynamics (MD) simulation. By applying constant or alternating biasing voltages, we found that the dsDNA molecule can be unzipped at the junction of the Y-CNT. Because of the energy barrier (a few k B T per base-pair), the motion of the entire DNA molecule was alternatively in a trapped state or a transiting state. We show that during each transiting state the same number of nucleotides were transported (DNA ratcheting). An analytical theory that is mathematically equivalent to the one for Josephson junctions was then proposed to quantitatively describe the simulation results. The controlled motion of DNA in the Y-CNT is expected to enhance the accuracy of nanopore-based DNA sequencing. † Electronic supplementary information (ESI) available: The movie showing MD trajectory of dsDNA translocation through a Y-pore (V bias ¼ 2 V). See
PLoS ONE, 2013
The recognition mechanism and cleavage activity of argonaute (Ago), miRNA, and mRNA complexes are... more The recognition mechanism and cleavage activity of argonaute (Ago), miRNA, and mRNA complexes are the core processes to the small non-coding RNA world. The 59 nucleation at the 'seed' region (position 2-8) of miRNA was believed to play a significant role in guiding the recognition of target mRNAs to the given miRNA family. In this paper, we have performed allatom molecular dynamics simulations of the related and recently revealed Ago-DNA:mRNA ternary complexes to study the dynamics of the guide-target recognition and the effect of mutations by introducing ''damaging'' C?C mismatches at different positions in the seed region of the DNA-RNA duplex. Our simulations show that the A-form-like helix duplex gradually distorts as the number of seed mismatches increases and the complex can survive no more than two such mismatches. Severe distortions of the guide-target heteroduplex are observed in the ruinous 4-sites mismatch mutant, which give rise to a bending motion of the PAZ domain along the L1/L2 ''hinge-like'' connection segment, resulting in the opening of the nucleic-acid-binding channel. These long-range interactions between the seed region and PAZ domain, moderated by the L1/L2 segments, reveal the central role of the seed region in the guide-target strands recognition: it not only determines the guide-target heteroduplex's nucleation and propagation, but also regulates the dynamic motions of Ago domains around the nucleic-acid-binding channel. Citation: Xia Z, Huynh T, Ren P, Zhou R (2013) Large Domain Motions in Ago Protein Controlled by the Guide DNA-Strand Seed Region Determine the Ago-DNA-mRNA Complex Recognition Process. PLoS ONE 8(1): e54620.
Scientific Reports, 2013
Age-onset cataracts are believed to be expedited by the accumulation of UV-damaged human cD-cryst... more Age-onset cataracts are believed to be expedited by the accumulation of UV-damaged human cD-crystallins in the eye lens. Here we show with molecular dynamics simulations that the stability of cD-crystallin is greatly reduced by the conversion of tryptophan to kynurenine due to UV-radiation, consistent with previous experimental evidences. Furthermore, our atomic-detailed results reveal that kynurenine attracts more waters and other polar sidechains due to its additional amino and carbonyl groups on the damaged tryptophan sidechain, thus breaching the integrity of nearby dry center regions formed by the two Greek key motifs in each domain. The damaged tryptophan residues cause large fluctuations in the Tyr-Trp-Tyr sandwich-like hydrophobic clusters, which in turn break crucial hydrogen-bonds bridging two b-strands in the Greek key motifs at the ''tyrosine corner''. Our findings may provide new insights for understanding of the molecular mechanism of the initial stages of UV-induced cataractogenesis. C ataracts are the leading cause of impairment and loss of vision in older adults, affecting nearly 22 million Americans over the age of 40, and 51% of world population over the age of 65 (National Eye Institute: www.nei.nih.gov and Prevent Blindness America www.preventblindness.org). Pathological studies have revealed that cataracts are associated with the aggregation of major lens proteins, the bc-crystallin family 1 . Because no protein turnover occurs in the lens core, the accumulation of insoluble aggregates of crystallin scatters incident light, reducing the light focused on the photoreceptors in the retina 2-6 .
Scientific Reports, 2012
To better understand the recognition mechanism of RISC and the repertoire of guide-target interac... more To better understand the recognition mechanism of RISC and the repertoire of guide-target interactions we introduced G:U wobbles and mismatches at various positions of the microRNA (miRNA) 'seed' region and performed all-atom molecular dynamics simulations of the resulting Ago-miRNA:mRNA ternary complexes. Our simulations reveal that many modifications, including combinations of multiple G:U wobbles and mismatches in the seed region, are admissible and result in only minor structural fluctuations that do not affect overall complex stability. These results are further supported by analyses of HITS-CLIP data. Lastly, introduction of disruptive mutations revealed a bending motion of the PAZ domain along the L1/L2 'hinge' and a subsequent opening of the nucleic-acid-binding channel. Our findings suggest that the spectrum of a miRNA's admissible targets is different from what is currently anticipated by the canonical seed-model. Moreover, they provide a likely explanation for the previously reported sequence-dependent regulation of unintended targeting by siRNAs. SUBJECT AREAS: RNAI NON-CODING RNA'S SMALL RNA'S GENE EXPRESSION
Scientific Reports, 2012
Endohedral metallofullerenol Gd@C 82 (OH) 22 has recently been shown to effectively inhibit tumor... more Endohedral metallofullerenol Gd@C 82 (OH) 22 has recently been shown to effectively inhibit tumor growth; however, its potential adverse bioeffects remain to be understood before its wider applications. Here, we present our study on the interaction between Gd@C 82 (OH) and WW domain, a representative protein domain involved in signaling and regulatory pathway, using all-atom explicit solvent molecular dynamics simulations. We find that Gd@C 82 (OH) 22 has an intrinsic binding preference to the binding groove, particularly the key signature residues Y28 and W39. In its binding competition with the native ligand PRM, Gd@C 82 (OH) 22 is shown to easily win the competition over PRM in occupying the active site, implying that Gd@C 82 (OH) 22 can impose a potential inhibitory effect on the WW domain. Further analyses with binding free energy landscapes reveal that Gd@C 82 (OH) can not only directly block the binding site of the WW domain, but also effectively distract the PRM from its native binding pocket. C arbone-based nanomaterials such as fullerenes and their derivatives have been widely used in de novo designs of nanoelectronics and nanomechanics due to their unique optoelectronic and physicochemical properties 1-3 . Advances in the biomedical science are particularly impressive in recent years, including applications in diagnostics as well as therapeutics for fatal diseases such as pancreatic cancer 4,5 . Although such success based on the nanotechnology has been referred to as a new medical paradigm, there is a growing concern on their potential adverse biological effects, which deserves an equal attention 6,7 . For example, CNTs can penetrate the cell membranes and accumulate in the cytoplasm, causing the cell death 8 . Meanwhile, functionalized CNTs can interact with the protein enzyme a-chymotrypsin and inhibit its enzymatic activity 9 . More recently, we find that the blood serum protein coated CNTs (protein-corona) are still toxic to various cell lines, though the cytotoxicity is reduced somewhat 10 . To make the situation more complicated, different experiments often show very different and controversial bioeffects, depending on their action context (i.e., in vitro, in vivo, target organs, interacting molecules, etc.). A fullerenol C 60 (OH) 24 has been shown to be less toxic than its pristine form C 60 with in vitro keratinocyte and hepatocyte cell lines 11 , as it is generally perceived that a fullerene decreases its toxicity with the increase of its surface functionalization. While a following study observed no toxicity with both fullerene and its fullerenol-derivative in rats exposed via intratracheal instillation 12 . Furthermore, another study showed that the fullerenol (i.e., C 60 (OH) 18 ) was more toxic than C 60 although both elicite membrane damage in isolated rat liver microsomes 13 . These studies demonstrate that the pharmacokinetics of nanoparticles are more complicated than previously thought, and are often difficult to extrapolate from one evidence, thus necessitating molecular level understanding of the detailed mechanism 14 .
Scientific Reports, 2014
Cancer metastasis is an important criterion to evaluate tumor malignancy. Matrix metalloproteinas... more Cancer metastasis is an important criterion to evaluate tumor malignancy. Matrix metalloproteinases (MMPs) play a crucial role in cancer proliferation and migration by virtue of their proteolytic functions in angiogenesis and extracelluar matrix (ECM) degradation, making them potential targets of anti-metastaic therapeutics. Recently we showed with both in vivo and in vitro experiments that metallofullerenol Gd@ C 82 (OH) 22 can effectively inhibit MMP-2 and MMP-9 with high antitumoral efficacy. Furthermore, our in silico study revealed that Gd@C 82 (OH) 22 could indirectly inhibit the proteolysis of MMP-9 via allosteric modulation exclusively at the ligand specificity S19 loop. Here, we expand our study toward another gelatinase, MMP-2, using molecular dynamics simulations. Despite the high structural similarity with 64.3% sequence identity, their responses to Gd@C 82 (OH) 22 were quite different. Toward MMP-2, Gd@ C 82 (OH) 22 could block either the Zn 21 -catalylitic site directly or the S19 loop indirectly. Surface electrostatics uniquely determines the initial adsorption of Gd@C 82 (OH) 22 on MMP-2, and then its further location of the most favorable binding site(s). These findings not only illustrated how the inhibitory mechanism of Gd@C 82 (OH) 22 is distinguished between the two gelatinase MMPs with atomic details, but also shed light on the de novo design of anti-metastatic nanotherapeutics with enhanced target specificity.
Nanoscale, 2014
Ultraviolet-radiation-induced damage to and aggregation of human lens crystallin proteins are tho... more Ultraviolet-radiation-induced damage to and aggregation of human lens crystallin proteins are thought to be a significant pathway to age-related cataract. The aromatic residues within the duplicated Greek key domains of γ- and β-crystallins are the main ultraviolet absorbers and are susceptible to direct and indirect ultraviolet damage. The previous site-directed mutagenesis studies have revealed a striking difference for two highly conserved homologous β-hairpin Tyr pairs, at the N-terminal domain (N-td) and C-terminal domain (C-td), respectively, in their contribution to the overall stability of HγD-Crys, but why they behave so differently still remains a mystery. In this paper, we systematically investigated the underlying molecular mechanism and detailed contributions of these two Tyr pairs with large scale molecular dynamics simulations. A series of different tyrosine-to-alanine pair(s) substitutions were performed in either the N-td, the C-td, or both. Our results suggest that the Y45A/Y50A pair substitution in the N-td mainly affects the stability of the N-td itself, while the Y133A/Y138A pair substitution in the C-td leads to a more cooperative unfolding of both N-td and C-td. The stability of motif 2 in the N-td is mainly determined by the interdomain interface, while motif 1 in the N-td or motifs 3 and 4 in the C-td are mainly stabilized by the intradomain hydrophobic core. The damage to any tyrosine pair(s) can directly introduce some apparent water leakage to the hydrophobic core at the interface, which in turn causes a serious loss in the stability of the N-td. However, for the C-td substitutions, it may further impair the stable "sandwich-like" Y133-R167-Y138 cluster (through cation-π interactions) in the wild-type, thus causing the loop regions near the residue A138 to undergo large fluctuations, which in turn results in the intrusion of water into the hydrophobic core of the C-td and induces the C-td to lose its stability. These findings help resolve the "mystery" on why these two Tyr pairs display such a striking difference in their contributions to the overall protein stability despite their highly homologous nature.
Nanoscale, 2013
Biocompatibility is often regarded as one important aspect of de novo designed nanomaterials for ... more Biocompatibility is often regarded as one important aspect of de novo designed nanomaterials for biosafety. However, the toxicological effect, appearing along with its latency, is much more difficult to address by linearly mapping physicochemical properties of related nanomaterials with biological effects such as immune or cellular regulatory responses due to the complicated protein-protein interactions. Here, we investigate a potential interference of a metallofullerenol, Gd@C82(OH)22, on the function of SH3 domain, a highly promiscuous protein-protein interaction mediator involved in signaling and regulatory pathways through its binding with the proline-rich motif (PRM) peptides, using the atomistic molecular dynamics simulation. Our study shows that when only Gd@C82(OH)22 and the SH3 domain are present (without the PRM ligand), Gd@C82(OH)22 can interact with the SH3 domain by either directly blocking the hydrophobic active site or binding with a hydrophilic off-site with almost equal probability, which can be understood from its intrinsic amphiphilic nature. In a binding competition with the PRM onto the SH3 domain, however, the on-site binding mode is depleted while Gd@C82(OH)22 effectively intercepts the PRM from the putative binding site of the SH3 domain, implying that Gd@C82(OH)22 can disturb protein-protein interactions mediated by the SH3 domain. Despite a successful surface modification in an aqueous biological medium and a more recent demonstration as potential de novo cancer therapeutics, our study indicates that greater attention is needed in assessing the potential cytotoxicity of these nanomaterials.
Biophysical Journal, 2012
Antibodies binding to conserved epitopes can provide a broad range of neutralization to existing ... more Antibodies binding to conserved epitopes can provide a broad range of neutralization to existing influenza subtypes and may also prevent the propagation of potential pandemic viruses by fighting against emerging strands. Here we propose a computational framework to study structural binding patterns and detailed molecular mechanisms of viral surface glycoprotein hemagglutinin (HA) binding with a broad spectrum of neutralizing monoclonal antibody fragments (Fab). We used rigorous free-energy perturbation (FEP) methods to calculate the antigen-antibody binding affinities, with an aggregate underlying molecular-dynamics simulation time of several microseconds (~2 ms) using all-atom, explicit-solvent models. We achieved a high accuracy in the validation of our FEP protocol against a series of known binding affinities for this complex system, with <0.5 kcal/mol errors on average. We then introduced what to our knowledge are novel mutations into the interfacial region to further study the binding mechanism. We found that the stacking interaction between Trp-21 in HA2 and Phe-55 in the CDR-H2 of Fab is crucial to the antibody-antigen association. A single mutation of either W21A or F55A can cause a binding affinity decrease of DDG > 4.0 kcal/mol (equivalent to an~1000-fold increase in the dissociation constant K d ). Moreover, for group 1 HA subtypes (which include both the H1N1 swine flu and the H5N1 bird flu), the relative binding affinities change only slightly (< 51 kcal/mol) when nonpolar residues at the aA helix of HA mutate to conservative amino acids of similar size, which explains the broad neutralization capability of antibodies such as F10 and CR6261. Finally, we found that the hydrogen-bonding network between His-38 (in HA1) and Ser-30/Gln-64 (in Fab) is important for preserving the strong binding of Fab against group 1 HAs, whereas the lack of such hydrogen bonds with Asn-38 in most group 2 HAs may be responsible for the escape of antibody neutralization. These large-scale simulations may provide new insight into the antigen-antibody binding mechanism at the atomic level, which could be essential for designing more-effective vaccines for influenza.
ACS Nano, 2012
A surprising &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp... more A surprising &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;upright&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; fibrilar conformation (with a height of ~2.6 nm) was observed with in situ atomic force microscopy (AFM) for an amyloid-like peptide (NH(2)-VGGAVVAV-COHN(2)) on mica surface, which is very different from its &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;flat&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; conformation (with a much smaller height of ~0.9 nm) on the HOPG surface. Our all-atom molecular dynamics (MD) simulations reveal that it is the strong electrostatic interactions between the N-terminus of the peptide and the mica surface that result in an upright conformation and a highly ordered β-stranded structure on mica, with a height of 2.5 ± 0.1 nm, consistent with the AFM experiment. Similarly, our MD simulations show that the same peptides adopt a flat conformation on HOPG surfaces due to the favorable hydrophobic interactions with HOPG. Our simulations also indicate that epitaxial patterns found in mica are preferentially controlled by anisotropic binding sites commensurate with the inherent crystallographic unit cell of the basal substrate.
Lecture Notes in Computer Science, 1990
We address the problem of building intelligent query systems to reason about linear arithmetic co... more We address the problem of building intelligent query systems to reason about linear arithmetic constraints. The central issue is the development of tools for testing solvability, for constraints representation, for incremental updates and for intelligent feedback. The ...
Lecture Notes in Computer Science, 1990
Only comparatively recently, Fourier solvability algorithm for linear constraints has been shown ... more Only comparatively recently, Fourier solvability algorithm for linear constraints has been shown to be of great theoretical interest in Linear Programming: the fundamental duality theorem and other major results are a direct consequence of it. We show here that Fourier ...
Annals of Mathematics and Artificial Intelligence, 1992
Projection of polyhedral sets is a fundamental operation in both geometry and symbolic computatio... more Projection of polyhedral sets is a fundamental operation in both geometry and symbolic computation. In most cases, however, it is not practically feasible to generate projections as the size of the output can be exponential in the size of the input. Even when the size of the ...
ACS Nano, 2015
While carbon-based nanomaterials such as graphene and carbon nanotubes (CNTs) have become popular... more While carbon-based nanomaterials such as graphene and carbon nanotubes (CNTs) have become popular in state-of-the-art nanotechnology, their biological safety and underlying molecular mechanism is still largely unknown. Experimental studies have been focused at the cellular level and revealed good correlations between cell&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s death and the application of CNTs or graphene. Using large-scale all-atom molecular dynamics simulations, we theoretically investigate the potential toxicity of graphene to a biological cell at molecular level. Simulation results show that the hydrophobic protein-protein interaction (or recognition) that is essential to biological functions can be interrupted by a graphene nanosheet. Due to the hydrophobic nature of graphene, it is energetically favorable for a graphene nanosheet to enter the hydrophobic interface of two contacting proteins, such as a dimer. The forced separation of two functional proteins can disrupt the cell&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s metabolism and even lead to the cell&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s mortality.
The Journal of Physical Chemistry Letters, 2015
Developing a low-cost and high-efficacy method to optimize prescreened or designed drug candidate... more Developing a low-cost and high-efficacy method to optimize prescreened or designed drug candidates will facilitate drug discovery and biomedical research in general. Current methods of drug screening usually involve tedious sample preparation and costly biological/chemical assays. Here, through all-atom molecular dynamics simulations, we propose a new drug optimization method, based on the nanopore force spectroscopy, to electrically detect the binding strength between a drug molecule and a target protein. Simulation results demonstrate that the drug-protein complex can be electrophoretically driven into a nanopore, which is followed by the rupture of the complex at a critical biasing voltage. The latter determines the binding strength of the tested drug molecule. It is expected that the application of this single-molecule technology could help to accelerate the drug discovery, particularly for processes of the narrow screening and further lead optimization.
Nanoscale, 2014
We investigate the possible ratcheting dynamics of double-stranded DNA (dsDNA) driven through a Y... more We investigate the possible ratcheting dynamics of double-stranded DNA (dsDNA) driven through a Yshaped carbon nanotube (Y-CNT) in a solid membrane, using all-atom molecular dynamics (MD) simulation. By applying constant or alternating biasing voltages, we found that the dsDNA molecule can be unzipped at the junction of the Y-CNT. Because of the energy barrier (a few k B T per base-pair), the motion of the entire DNA molecule was alternatively in a trapped state or a transiting state. We show that during each transiting state the same number of nucleotides were transported (DNA ratcheting). An analytical theory that is mathematically equivalent to the one for Josephson junctions was then proposed to quantitatively describe the simulation results. The controlled motion of DNA in the Y-CNT is expected to enhance the accuracy of nanopore-based DNA sequencing. † Electronic supplementary information (ESI) available: The movie showing MD trajectory of dsDNA translocation through a Y-pore (V bias ¼ 2 V). See
PLoS ONE, 2013
The recognition mechanism and cleavage activity of argonaute (Ago), miRNA, and mRNA complexes are... more The recognition mechanism and cleavage activity of argonaute (Ago), miRNA, and mRNA complexes are the core processes to the small non-coding RNA world. The 59 nucleation at the 'seed' region (position 2-8) of miRNA was believed to play a significant role in guiding the recognition of target mRNAs to the given miRNA family. In this paper, we have performed allatom molecular dynamics simulations of the related and recently revealed Ago-DNA:mRNA ternary complexes to study the dynamics of the guide-target recognition and the effect of mutations by introducing ''damaging'' C?C mismatches at different positions in the seed region of the DNA-RNA duplex. Our simulations show that the A-form-like helix duplex gradually distorts as the number of seed mismatches increases and the complex can survive no more than two such mismatches. Severe distortions of the guide-target heteroduplex are observed in the ruinous 4-sites mismatch mutant, which give rise to a bending motion of the PAZ domain along the L1/L2 ''hinge-like'' connection segment, resulting in the opening of the nucleic-acid-binding channel. These long-range interactions between the seed region and PAZ domain, moderated by the L1/L2 segments, reveal the central role of the seed region in the guide-target strands recognition: it not only determines the guide-target heteroduplex's nucleation and propagation, but also regulates the dynamic motions of Ago domains around the nucleic-acid-binding channel. Citation: Xia Z, Huynh T, Ren P, Zhou R (2013) Large Domain Motions in Ago Protein Controlled by the Guide DNA-Strand Seed Region Determine the Ago-DNA-mRNA Complex Recognition Process. PLoS ONE 8(1): e54620.
Scientific Reports, 2013
Age-onset cataracts are believed to be expedited by the accumulation of UV-damaged human cD-cryst... more Age-onset cataracts are believed to be expedited by the accumulation of UV-damaged human cD-crystallins in the eye lens. Here we show with molecular dynamics simulations that the stability of cD-crystallin is greatly reduced by the conversion of tryptophan to kynurenine due to UV-radiation, consistent with previous experimental evidences. Furthermore, our atomic-detailed results reveal that kynurenine attracts more waters and other polar sidechains due to its additional amino and carbonyl groups on the damaged tryptophan sidechain, thus breaching the integrity of nearby dry center regions formed by the two Greek key motifs in each domain. The damaged tryptophan residues cause large fluctuations in the Tyr-Trp-Tyr sandwich-like hydrophobic clusters, which in turn break crucial hydrogen-bonds bridging two b-strands in the Greek key motifs at the ''tyrosine corner''. Our findings may provide new insights for understanding of the molecular mechanism of the initial stages of UV-induced cataractogenesis. C ataracts are the leading cause of impairment and loss of vision in older adults, affecting nearly 22 million Americans over the age of 40, and 51% of world population over the age of 65 (National Eye Institute: www.nei.nih.gov and Prevent Blindness America www.preventblindness.org). Pathological studies have revealed that cataracts are associated with the aggregation of major lens proteins, the bc-crystallin family 1 . Because no protein turnover occurs in the lens core, the accumulation of insoluble aggregates of crystallin scatters incident light, reducing the light focused on the photoreceptors in the retina 2-6 .
Scientific Reports, 2012
To better understand the recognition mechanism of RISC and the repertoire of guide-target interac... more To better understand the recognition mechanism of RISC and the repertoire of guide-target interactions we introduced G:U wobbles and mismatches at various positions of the microRNA (miRNA) 'seed' region and performed all-atom molecular dynamics simulations of the resulting Ago-miRNA:mRNA ternary complexes. Our simulations reveal that many modifications, including combinations of multiple G:U wobbles and mismatches in the seed region, are admissible and result in only minor structural fluctuations that do not affect overall complex stability. These results are further supported by analyses of HITS-CLIP data. Lastly, introduction of disruptive mutations revealed a bending motion of the PAZ domain along the L1/L2 'hinge' and a subsequent opening of the nucleic-acid-binding channel. Our findings suggest that the spectrum of a miRNA's admissible targets is different from what is currently anticipated by the canonical seed-model. Moreover, they provide a likely explanation for the previously reported sequence-dependent regulation of unintended targeting by siRNAs. SUBJECT AREAS: RNAI NON-CODING RNA'S SMALL RNA'S GENE EXPRESSION
Scientific Reports, 2012
Endohedral metallofullerenol Gd@C 82 (OH) 22 has recently been shown to effectively inhibit tumor... more Endohedral metallofullerenol Gd@C 82 (OH) 22 has recently been shown to effectively inhibit tumor growth; however, its potential adverse bioeffects remain to be understood before its wider applications. Here, we present our study on the interaction between Gd@C 82 (OH) and WW domain, a representative protein domain involved in signaling and regulatory pathway, using all-atom explicit solvent molecular dynamics simulations. We find that Gd@C 82 (OH) 22 has an intrinsic binding preference to the binding groove, particularly the key signature residues Y28 and W39. In its binding competition with the native ligand PRM, Gd@C 82 (OH) 22 is shown to easily win the competition over PRM in occupying the active site, implying that Gd@C 82 (OH) 22 can impose a potential inhibitory effect on the WW domain. Further analyses with binding free energy landscapes reveal that Gd@C 82 (OH) can not only directly block the binding site of the WW domain, but also effectively distract the PRM from its native binding pocket. C arbone-based nanomaterials such as fullerenes and their derivatives have been widely used in de novo designs of nanoelectronics and nanomechanics due to their unique optoelectronic and physicochemical properties 1-3 . Advances in the biomedical science are particularly impressive in recent years, including applications in diagnostics as well as therapeutics for fatal diseases such as pancreatic cancer 4,5 . Although such success based on the nanotechnology has been referred to as a new medical paradigm, there is a growing concern on their potential adverse biological effects, which deserves an equal attention 6,7 . For example, CNTs can penetrate the cell membranes and accumulate in the cytoplasm, causing the cell death 8 . Meanwhile, functionalized CNTs can interact with the protein enzyme a-chymotrypsin and inhibit its enzymatic activity 9 . More recently, we find that the blood serum protein coated CNTs (protein-corona) are still toxic to various cell lines, though the cytotoxicity is reduced somewhat 10 . To make the situation more complicated, different experiments often show very different and controversial bioeffects, depending on their action context (i.e., in vitro, in vivo, target organs, interacting molecules, etc.). A fullerenol C 60 (OH) 24 has been shown to be less toxic than its pristine form C 60 with in vitro keratinocyte and hepatocyte cell lines 11 , as it is generally perceived that a fullerene decreases its toxicity with the increase of its surface functionalization. While a following study observed no toxicity with both fullerene and its fullerenol-derivative in rats exposed via intratracheal instillation 12 . Furthermore, another study showed that the fullerenol (i.e., C 60 (OH) 18 ) was more toxic than C 60 although both elicite membrane damage in isolated rat liver microsomes 13 . These studies demonstrate that the pharmacokinetics of nanoparticles are more complicated than previously thought, and are often difficult to extrapolate from one evidence, thus necessitating molecular level understanding of the detailed mechanism 14 .
Scientific Reports, 2014
Cancer metastasis is an important criterion to evaluate tumor malignancy. Matrix metalloproteinas... more Cancer metastasis is an important criterion to evaluate tumor malignancy. Matrix metalloproteinases (MMPs) play a crucial role in cancer proliferation and migration by virtue of their proteolytic functions in angiogenesis and extracelluar matrix (ECM) degradation, making them potential targets of anti-metastaic therapeutics. Recently we showed with both in vivo and in vitro experiments that metallofullerenol Gd@ C 82 (OH) 22 can effectively inhibit MMP-2 and MMP-9 with high antitumoral efficacy. Furthermore, our in silico study revealed that Gd@C 82 (OH) 22 could indirectly inhibit the proteolysis of MMP-9 via allosteric modulation exclusively at the ligand specificity S19 loop. Here, we expand our study toward another gelatinase, MMP-2, using molecular dynamics simulations. Despite the high structural similarity with 64.3% sequence identity, their responses to Gd@C 82 (OH) 22 were quite different. Toward MMP-2, Gd@ C 82 (OH) 22 could block either the Zn 21 -catalylitic site directly or the S19 loop indirectly. Surface electrostatics uniquely determines the initial adsorption of Gd@C 82 (OH) 22 on MMP-2, and then its further location of the most favorable binding site(s). These findings not only illustrated how the inhibitory mechanism of Gd@C 82 (OH) 22 is distinguished between the two gelatinase MMPs with atomic details, but also shed light on the de novo design of anti-metastatic nanotherapeutics with enhanced target specificity.
Nanoscale, 2014
Ultraviolet-radiation-induced damage to and aggregation of human lens crystallin proteins are tho... more Ultraviolet-radiation-induced damage to and aggregation of human lens crystallin proteins are thought to be a significant pathway to age-related cataract. The aromatic residues within the duplicated Greek key domains of γ- and β-crystallins are the main ultraviolet absorbers and are susceptible to direct and indirect ultraviolet damage. The previous site-directed mutagenesis studies have revealed a striking difference for two highly conserved homologous β-hairpin Tyr pairs, at the N-terminal domain (N-td) and C-terminal domain (C-td), respectively, in their contribution to the overall stability of HγD-Crys, but why they behave so differently still remains a mystery. In this paper, we systematically investigated the underlying molecular mechanism and detailed contributions of these two Tyr pairs with large scale molecular dynamics simulations. A series of different tyrosine-to-alanine pair(s) substitutions were performed in either the N-td, the C-td, or both. Our results suggest that the Y45A/Y50A pair substitution in the N-td mainly affects the stability of the N-td itself, while the Y133A/Y138A pair substitution in the C-td leads to a more cooperative unfolding of both N-td and C-td. The stability of motif 2 in the N-td is mainly determined by the interdomain interface, while motif 1 in the N-td or motifs 3 and 4 in the C-td are mainly stabilized by the intradomain hydrophobic core. The damage to any tyrosine pair(s) can directly introduce some apparent water leakage to the hydrophobic core at the interface, which in turn causes a serious loss in the stability of the N-td. However, for the C-td substitutions, it may further impair the stable &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;sandwich-like&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; Y133-R167-Y138 cluster (through cation-π interactions) in the wild-type, thus causing the loop regions near the residue A138 to undergo large fluctuations, which in turn results in the intrusion of water into the hydrophobic core of the C-td and induces the C-td to lose its stability. These findings help resolve the &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;mystery&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; on why these two Tyr pairs display such a striking difference in their contributions to the overall protein stability despite their highly homologous nature.
Nanoscale, 2013
Biocompatibility is often regarded as one important aspect of de novo designed nanomaterials for ... more Biocompatibility is often regarded as one important aspect of de novo designed nanomaterials for biosafety. However, the toxicological effect, appearing along with its latency, is much more difficult to address by linearly mapping physicochemical properties of related nanomaterials with biological effects such as immune or cellular regulatory responses due to the complicated protein-protein interactions. Here, we investigate a potential interference of a metallofullerenol, Gd@C82(OH)22, on the function of SH3 domain, a highly promiscuous protein-protein interaction mediator involved in signaling and regulatory pathways through its binding with the proline-rich motif (PRM) peptides, using the atomistic molecular dynamics simulation. Our study shows that when only Gd@C82(OH)22 and the SH3 domain are present (without the PRM ligand), Gd@C82(OH)22 can interact with the SH3 domain by either directly blocking the hydrophobic active site or binding with a hydrophilic off-site with almost equal probability, which can be understood from its intrinsic amphiphilic nature. In a binding competition with the PRM onto the SH3 domain, however, the on-site binding mode is depleted while Gd@C82(OH)22 effectively intercepts the PRM from the putative binding site of the SH3 domain, implying that Gd@C82(OH)22 can disturb protein-protein interactions mediated by the SH3 domain. Despite a successful surface modification in an aqueous biological medium and a more recent demonstration as potential de novo cancer therapeutics, our study indicates that greater attention is needed in assessing the potential cytotoxicity of these nanomaterials.
Biophysical Journal, 2012
Antibodies binding to conserved epitopes can provide a broad range of neutralization to existing ... more Antibodies binding to conserved epitopes can provide a broad range of neutralization to existing influenza subtypes and may also prevent the propagation of potential pandemic viruses by fighting against emerging strands. Here we propose a computational framework to study structural binding patterns and detailed molecular mechanisms of viral surface glycoprotein hemagglutinin (HA) binding with a broad spectrum of neutralizing monoclonal antibody fragments (Fab). We used rigorous free-energy perturbation (FEP) methods to calculate the antigen-antibody binding affinities, with an aggregate underlying molecular-dynamics simulation time of several microseconds (~2 ms) using all-atom, explicit-solvent models. We achieved a high accuracy in the validation of our FEP protocol against a series of known binding affinities for this complex system, with <0.5 kcal/mol errors on average. We then introduced what to our knowledge are novel mutations into the interfacial region to further study the binding mechanism. We found that the stacking interaction between Trp-21 in HA2 and Phe-55 in the CDR-H2 of Fab is crucial to the antibody-antigen association. A single mutation of either W21A or F55A can cause a binding affinity decrease of DDG > 4.0 kcal/mol (equivalent to an~1000-fold increase in the dissociation constant K d ). Moreover, for group 1 HA subtypes (which include both the H1N1 swine flu and the H5N1 bird flu), the relative binding affinities change only slightly (< 51 kcal/mol) when nonpolar residues at the aA helix of HA mutate to conservative amino acids of similar size, which explains the broad neutralization capability of antibodies such as F10 and CR6261. Finally, we found that the hydrogen-bonding network between His-38 (in HA1) and Ser-30/Gln-64 (in Fab) is important for preserving the strong binding of Fab against group 1 HAs, whereas the lack of such hydrogen bonds with Asn-38 in most group 2 HAs may be responsible for the escape of antibody neutralization. These large-scale simulations may provide new insight into the antigen-antibody binding mechanism at the atomic level, which could be essential for designing more-effective vaccines for influenza.
ACS Nano, 2012
A surprising &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp... more A surprising &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;upright&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; fibrilar conformation (with a height of ~2.6 nm) was observed with in situ atomic force microscopy (AFM) for an amyloid-like peptide (NH(2)-VGGAVVAV-COHN(2)) on mica surface, which is very different from its &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;flat&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; conformation (with a much smaller height of ~0.9 nm) on the HOPG surface. Our all-atom molecular dynamics (MD) simulations reveal that it is the strong electrostatic interactions between the N-terminus of the peptide and the mica surface that result in an upright conformation and a highly ordered β-stranded structure on mica, with a height of 2.5 ± 0.1 nm, consistent with the AFM experiment. Similarly, our MD simulations show that the same peptides adopt a flat conformation on HOPG surfaces due to the favorable hydrophobic interactions with HOPG. Our simulations also indicate that epitaxial patterns found in mica are preferentially controlled by anisotropic binding sites commensurate with the inherent crystallographic unit cell of the basal substrate.