Binding Preference of Carbon Nanotube Over Proline-Rich Motif Ligand on SH3-Domain: A Comparison with Different Force Fields

With the widespread applications of nanomaterials such as carbon nanotubes, there is a growing concern on the biosafety of these engineered nanoparticles, in particular their interactions with proteins. In molecular simulations of nanoparticle–protein interactions, the choice of empirical parameters (force fields) plays a decisive role, and thus is of great importance and should be examined carefully before wider applications. Here we compare three commonly used force fields, CHARMM, OPLSAA, and AMBER in study of the competitive binding of a single wall carbon nanotube (SWCNT) with a native proline-rich motif (PRM) ligand on its target protein SH3 domain, a ubiquitous protein–protein interaction mediator involved in signaling and regulatory pathways. We find that the SWCNT displays a general preference over the PRM in binding with SH3 domain in all the three force fields examined, although the degree of preference can be somewhat different, with the AMBER force field showing the highest preference. The SWCNT prevents the ligand from reaching its native binding pocket by (i) occupying the binding pocket directly, and (ii) binding with the ligand itself and then being trapped together onto some off-sites. The π–π stacking interactions between the SWCNT and aromatic residues are found to play a significant role in its binding to the SH3 domain in all the three force fields. Further analyses show that even the SWCNT-ligand binding can also be relatively more stable than the native ligand-protein binding, indicating a serious potential disruption to the protein SH3 function

Coherent Microscopic Picture for Urea-Induced Denaturation of Proteins

In a previous study, we explored the mechanism of urea-induced denaturation of proteins by performing molecular dynamics (MD) simulations of hen lysozyme in 8 M urea and supported the “direct interaction mechanism” whereby urea denatures protein via dispersion interaction (Hua, L.; Zhou, R. H.; Thirumalai, D.; Berne, B. J. <i>Proc. Natl. Acad. Sci. U.S.A.</i> <b>2008</b>, <i>105</i>, 16928). Here we perform large scale MD simulations of five representative protein/peptide systems in aqueous urea to investigate if the above mechanism is common to other proteins. In all cases, accumulations of urea around proteins/peptide are observed, suggesting that urea denatures proteins by directly attacking protein backbones and side chains rather than indirectly disrupting water structure as a “water breaker”. Consistent with our previous case study of lysozyme, the current energetic analyses with five protein/peptide systems reveal that urea’s preferential binding to proteins mainly comes from urea’s stronger dispersion interactions with proteins than with bulk solution, whereas the electrostatic (hydrogen-bonded) interactions only play a relatively minor (even negative) role during this denaturation process. Furthermore, the simulations of the peptide system at different urea concentrations (8 and 4.5 M), and with different force fields (CHARMM and OPLSAA) suggest that the above mechanism is robust, independent of the urea concentration and force field used. Last, we emphasize the importance of periodic boundary conditions in pairwise energetic analyses. This article provides a comprehensive study on the physical mechanism of urea-induced protein denaturation and suggests that the “dispersion-interaction-driven” mechanism should be general

DataSheet_1_A Dual-Band Model for the Vertical Distribution of Photosynthetically Available Radiation (PAR) in Stratified Waters.docx

Based on the optical properties of water constituents, the vertical variation of photosynthetically available radiation (PAR) can be well modeled with hyperspectral resolution; the intensive computing load, however, demands simplified modeling that can be easily embedded in marine physical and biogeochemical models. While the vertical PAR profile in homogeneous waters can now be accurately modeled with simple parameterization, it is still a big challenge to model the PAR profile in stratified waters with limited variables. In this study, based on empirical equations and simulations, we propose a dual-band model to characterize the vertical distribution of PAR using the chlorophyll concentration (Chl). With an inclusive dataset including cruise data collected in the Southeast Pacific and BGC-Argo data in the global ocean, the model was thoroughly evaluated for its general applicability in three aspects: 1) estimating the entire PAR profile from sea-surface PAR and the Chl profile, 2) estimating the euphotic layer depth from the Chl profile, and 3) estimating PAR just below the sea surface from in situ radiometry measurements. It is demonstrated that the proposed dual-band model is capable of generating similar estimates as that from a hyperspectral model, thus offering an effective module that can be incorporated in large-scale ecosystem and/or circulation models for efficient calculations.</p

Dewetting Transitions in the Self-Assembly of Two Amyloidogenic β-Sheets and the Importance of Matching Surfaces

We use molecular dynamics simulations to investigate the water-mediated self-assembly of two amyloidogenic β-sheets of hIAPP22–27 peptides (NFGAIL). The initial configurations of β-sheet pairs are packed with two different modes, forming a tube-like nanoscale channel and a slab-like 2-D confinement, respectively. For both packing modes, we observe strong water drying transitions occurring in the intersheet region with high occurrence possibilities, suggesting that the “dewetting transition”-induced collapse may play an important role in promoting the amyloid fibrils formation. However, contrary to general dewetting theory prediction, the slab-like confinement (2-D) shows stronger dewetting phenomenon than the tube-like channel (1-D). This unexpected observation is attributed to the different surface roughness caused by different packing modes. Furthermore, we demonstrated the profound influence of internal surface topology of β-sheet pairs on the dewetting phenomenon through an in silico mutagenesis study. The present study highlights the important role of packing modes (i.e., surface roughness) in the assembly process of β-sheets, which improves our understanding toward the molecular mechanism of the amyloid fibrils formation. In addition, our study also suggests a potential route to regulate controllably the self-assembly process of β-sheets through mutations, which may have future applications in nanotechnology and biotechnology

DataSheet_1_Unraveling environmental drivers of chlorophyll seasonal and interannual variability in the East China Sea.docx

Phytoplankton, the dominant marine primary producers, are considered highly sensitive indicators of ecosystem conditions and changes. The East China Sea (ECS) includes a variety of oceanic and coastal domains that collectively challenge our understanding of phytoplankton dynamics and controls. This study evaluates the seasonal and interannual variability of phytoplankton in the ECS and the underlying environmental determinants based on 22-year satellite chlorophyll (Chl-a) data and concurrent environmental variables. A seasonal spring bloom was found in the ECS, classically driven by increased stratification, which is associated with increases in sea surface temperature (SST), photosynthetically available radiation (PAR), net heat flux (NHF), and reduced wind mixing. The most significant Chl-a interannual variability was present in a triangular area surrounded by three SST fronts in the southern ECS during springtime. Anomalously high Chl-a (~30% increase) occurred with increased SST and NHF and enhanced wind mixing during negative Pacific Decadal Oscillation (PDO) and El Niño–Southern Oscillation (ENSO) modes. This seems to be contrary to the stratification control model, which fits the seasonal spring bloom observed in this region. More front activities during the negative PDO and ENSO could be associated with Chl-a increase in this triangular area. Contrary to this mixing control scenario, a significant Chl-a increase (~36% increase) also developed during the positive PDO and ENSO modes after 2014 under conditions of higher SST, NHF, and weaker wind mixing following the stratification control scenario. This study used biologically relevant objective regionalization of a heterogeneous area to elucidate phytoplankton bloom dynamics and controls. Our analyses highlight the triangular area in the ECS for its region-specific linkages between Chl-a and multiple climate-sensitive environmental drivers, as well as the potential structural and functional variability in this region.</p

Data_Sheet_1_Roles of Iron Limitation in Phytoplankton Dynamics in the Western and Eastern Subarctic Pacific.docx

The subarctic Pacific is one of the major high-nitrate, low-chlorophyll (HNLC) regions where marine productivity is greatly limited by the supply of iron (Fe) in the region. There is a distinct seasonal difference in the chlorophyll concentrations of the east and west sides of the subarctic Pacific because of the differences in their driving mechanisms. In the western subarctic Pacific, two chlorophyll concentration peaks occur: the peak in spring and early summer is dominated by diatoms, while the peak in late summer and autumn is dominated by small phytoplankton. In the eastern subarctic Pacific, a single chlorophyll concentration peak occurs in late summer, while small phytoplankton dominate throughout the year. In this study, two one-dimensional (1D) physical–biological models with Fe cycles were applied to Ocean Station K2 (Stn. K2) in the western subarctic Pacific and Ocean Station Papa (Stn. Papa) in the eastern subarctic Pacific. These models were used to study the role of Fe limitation in regulating the seasonal differences in phytoplankton populations by reproducing the seasonal variability in ocean properties in each region. The results were reasonably comparable with observational data, i.e., cruise and Biogeochemical-Argo data, showing that the difference in bioavailable Fe (BFe) between Stn. K2 and Stn. Papa played a dominant role in controlling the respective seasonal variabilities of diatom and small phytoplankton growth. At Stn. Papa, there was less BFe, and the Fe limitation of diatom growth was two times as strong as that at Stn. K2; however, the difference in the Fe limitation of small phytoplankton growth between these two regions was relatively small. At Stn. K2, the decrease in BFe during summer reduced the growth rate of diatoms, which led to a rapid reduction in diatom biomass. Simultaneously, the decrease in BFe had little impact on small phytoplankton growth, which helped maintain the relatively high small phytoplankton biomass until autumn. The experiments that stimulated a further increase in atmospheric Fe deposition also showed that the responses of phytoplankton primary production in the eastern subarctic Pacific were stronger than those in the western subarctic Pacific but contributed little to primary production, as the Fe limitation of phytoplankton growth was replaced by macronutrient limitation.</p

Inhibition of Amyloid Nucleation by Steric Hindrance

Despite recent experiments and simulations suggesting that small-molecule inhibitors and some post-translational modifications (e.g., glycosylation and ubiquitination) can suppress the pathogenic aggregation of proteins due to steric hindrance, the effect of steric hindrance on amyloid formation has not been systematically studied. Based on Monte Carlo simulations using a coarse-grained model for amyloidogenic proteins and a hard sphere acting as steric hindrance, we investigated how steric hindrance on proteins could affect amyloid formation, particularly two steps of primary nucleation, namely, oligomerization and conformational conversion into a β-sheet-enriched nucleus. We found that steric spheres played an inhibitory role in oligomerization with the effect proportional to the sphere radius RS, which we attributed to the decline in the nonspecific attractions between proteins. During the second step, small steric spheres facilitated the conformational conversion of proteins while large ones suppressed the conversion. The overall steric effect on amyloid nucleation was inhibitory regardless of RS. As RS increased, oligomeric assemblies changed from amorphous into sheet-like, structurally ordered species, reminiscent of the structure of amyloid fibrils. The oligomers with large RS were off-pathway with their ordered structures induced by the competition between steric hindrance and nonspecific attractions of soluble proteins. Interestingly, the equimolar mixture of proteins with and without steric hindrance amplified the sterically inhibitory effect by increasing the energy barrier of protein’s conformational conversion. The physical mechanisms and biological implications of the above results are discussed. Our findings improve the current understanding of how nature regulates protein aggregation and amyloid formation by steric hindrance

Urea-Induced Drying of Hydrophobic Nanotubes: Comparison of Different Urea Models

In a previous study, we performed the molecular dynamics (MD) simulations of various carbon nanotubes solvated in 8 M urea and observed a striking phenomenon of urea-induced drying of hydrophobic nanotubes, which resulted from the stronger dispersion interaction of urea than water with nanotube (Das, P.; Zhou, R. H. J. Phys. Chem. B 2010, 114, 5427−5430). In this paper, we have compared five different urea models to investigate if the above phenomenon is sensitive to the urea models used. We demonstrate through MD simulations that the drying phenomenon and its physical mechanism are qualitatively independent of the urea models. Consistent with our previous study, our current analyses with both interaction potential energy and association free energy indicate that there is a “dry state” inside the carbon nanotubes, which is caused by the urea’s preferential binding to nanotubes through stronger dispersion interactions. These results also have implications for understanding the urea-induced protein denaturation by providing further evidence of the potential existence of a “dry globule”-like transient state during protein unfolding and the “direct interaction mechanism” (whereby urea attacks protein directly, rather than disrupts water structure as a “water breaker”). In addition, our study highlights the crucial role of dispersion interaction in the selective absorption of molecules in hydrophobic nanopores and may have significance for nanoscience and nanotechnology

Manipulating Biomolecules with Aqueous Liquids Confined within Single-Walled Nanotubes

Confinement of molecules inside nanoscale pores has become an important method for exploiting new dynamics not happening in bulk systems and for fabricating novel structures. Molecules that are encapsulated in nanopores are difficult to control with respect to their position and activity. On the basis of molecular dynamics simulations, we have achieved controllable manipulation, both in space and time, of biomolecules with aqueous liquids inside a single-walled nanotube by using an external charge or a group of external charges. The remarkable manipulation abilities are attributed to the single-walled structure of the nanotube that the electrostatic interactions of charges inside and outside the single-walled nanotube are strong enough, and the charge-induced dipole-orientation ordering of water confined in the nanochannel so that water has a strong interaction with the external charge. These designs are expected to serve as lab-in-nanotube for the interactions and chemical reactions of molecules especially biomolecules, and have wide applications in nanotechnology and biotechnology

Manipulating Biomolecules with Aqueous Liquids Confined within Single-Walled Nanotubes

Confinement of molecules inside nanoscale pores has become an important method for exploiting new dynamics not happening in bulk systems and for fabricating novel structures. Molecules that are encapsulated in nanopores are difficult to control with respect to their position and activity. On the basis of molecular dynamics simulations, we have achieved controllable manipulation, both in space and time, of biomolecules with aqueous liquids inside a single-walled nanotube by using an external charge or a group of external charges. The remarkable manipulation abilities are attributed to the single-walled structure of the nanotube that the electrostatic interactions of charges inside and outside the single-walled nanotube are strong enough, and the charge-induced dipole-orientation ordering of water confined in the nanochannel so that water has a strong interaction with the external charge. These designs are expected to serve as lab-in-nanotube for the interactions and chemical reactions of molecules especially biomolecules, and have wide applications in nanotechnology and biotechnology