Developing efficient deep learning model for predicting copolymer properties.

Deep learning models are gaining popularity and potency in predicting polymer properties. These models can be built using pre-existing data and are useful for the rapid prediction of polymer properties. However, the performance of a deep learning model is intricately connected to its topology and the volume of training data. There is no facile protocol available to select a deep learning architecture, and there is a lack of a large volume of homogeneous sequence-property data of polymers. These two factors are the primary bottleneck for the efficient development of deep learning models for polymers. Here we assess the severity of these factors and propose strategies to address them. We show that a linear layer-by-layer expansion of a neural network can help in identifying the best neural network topology for a given problem. Moreover, we map the discrete sequence space of a polymer to a continuous one-dimensional latent space using a feature extraction technique to identify minimal data points for training a deep learning model. We implement these approaches for two representative cases of building sequence-property surrogate models, viz., the single-molecule radius of gyration of a copolymer and copolymer compatibilizer. This work demonstrates efficient methods for building deep learning models with minimal data and hyperparameters for predicting sequence-defined properties of polymers.

Molecular simulation of the shape deformation of a polymersome.

Vesicles composed of diblock copolymers, or polymersomes, have proven to possess numerous applications ranging from drug delivery to catalytically driven nano-motors. The shape of a polymersome can be responsive to external stimuli, such as light or solvent. Molecular dynamics simulations reveal that the shape change upon the contraction of the inner volume of a polymersome vesicle occurs in two separate regimes-a stretching regime and a bending regime. The barrier is shown to be dependent on the solvent environment. These results suggest that tailoring the bending modulus of polymer membranes can be used as a design methodology to engineer new stimuli-responsive vesicles.

Glassy worm-like micelles in solvent and shear mediated shape transitions.

The glassiness of polymer melts is generally considered to be suppressed by small dimensions, added solvent, and heat. Here, we suggest that glassiness persists at the nanoscale in worm-like micelles composed of amphiphilic diblock copolymers of poly(ethylene oxide)-polystyrene (PS). The glassiness of these worms is indicated by a lack of fluorescence recovery after photobleaching as well as micron-length rigid segments separated by hinges. The coarse-grained molecular dynamics studies probe the dynamics of the PS in these glassy worms. Addition of an organic solvent promotes a transition from hinged to fully flexible worms and to spheres or vesicles. Simulation demonstrates two populations of organic solvent in the core of the micelle-a solvent 'pool' in the micelle core and a second population that accumulates at the interface between the core and the corona. The stable heterogeneity of the residual solvent could explain the unusual hinged rigidity, but solvent removal during shear-extension could be more effective and yield - as observed - nearly straight worms without hinges.

Molecular Dynamics Simulations of Supramolecular Anticancer Nanotubes.

We report here on long-time all-atomistic molecular dynamics simulations of functional supramolecular nanotubes composed by the self-assembly of peptide-drug amphiphiles (DAs). These DAs have been shown to possess an inherently high drug loading of the hydrophobic anticancer drug camptothecin. We probe the self-assembly mechanism from random with ∼0.4 µs molecular dynamics simulations. Furthermore, we also computationally characterize the interfacial structure, directionality of π-π stacking, and water dynamics within several peptide-drug nanotubes with diameters consistent with the reported experimental nanotube diameter. Insight gained should inform the future design of these novel anticancer drug delivery systems.

Molecular simulations of peptide amphiphiles.

This review describes recent progress in the area of molecular simulations of peptide assemblies, including peptide-amphiphiles and drug-amphiphiles. The ability to predict the structure and stability of peptide self-assemblies from the molecular level up is vital to the field of nanobiotechnology. Computational methods such as molecular dynamics offer the opportunity to characterize intermolecular forces between peptide-amphiphiles that are critical to the self-assembly process. Furthermore, these computational methods provide the ability to computationally probe the structure of these supramolecular assemblies at the molecular level, which is a challenge experimentally. Herein, we briefly highlight progress in the areas of all-atomistic and coarse-grained simulation studies investigating the self-assembly process of short peptides and peptide amphiphiles. We also discuss recent all-atomistic and coarse-grained simulations of the self-assembly of a drug-amphiphile into elongated filaments. Next, we discuss how these computational methods can provide further insight into the pathway of cylindrical nanofiber formation and predict their biocompatibility by studying the interaction of these peptide-amphiphile nanostructures with model cell membranes.

Microscopic understanding of the conformational features of a protein-DNA complex.

Protein-DNA interactions play crucial roles in different biological processes. Binding of a protein to its target DNA is the key step at different stages of genetic activities. In this article, we have carried out atomistic molecular dynamics simulations to understand the microscopic conformational and dynamical features of the N-terminal domain of the λ-repressor protein and its operator DNA in their complexed state. The calculations revealed that the overall flexibility of the protein and the DNA components reduces due to complex formation. In particular, increased ordering of the DNA sugar rings bound to the protein is found to be associated with modified ring puckering. Attempts have been made to study the effect of complexation on the internal motions of the protein and the DNA components. It is demonstrated that the non-uniform ordering of the side chains of lysine residues in the consensus sequence leads to differential behavior of the two monomers of the homodimeric protein.

Asymmetric breathing motions of nucleosomal DNA and the role of histone tails.

The most important packing unit of DNA in the eukaryotic cell is the nucleosome. It undergoes large-scale structural re-arrangements during different cell cycles. For example, the disassembly of the nucleosome is one of the key steps for DNA replication, whereas reassembly occurs after replication. Thus, conformational dynamics of the nucleosome is crucial for different DNA metabolic processes. We perform three different sets of atomistic molecular dynamics simulations of the nucleosome core particle at varying degrees of salt conditions for a total of 0.7 µs simulation time. We find that the conformational dynamics of the nucleosomal DNA tails are oppositely correlated from each other during the initial breathing motions. Furthermore, the strength of the interaction of the nucleosomal DNA tail with the neighboring H2A histone tail modulates the conformational state of the nucleosomal DNA tail. With increasing salt concentration, the degree of asymmetry in the conformation of the nucleosomal DNA tails decreases as both tails tend to unwrap. This direct correlation between the asymmetric breathing motions of the DNA tails and the H2A histone tails, and its decrease at higher salt concentrations, may play a significant role in the molecular pathway of unwrapping.

Exercise and eating habits among urban adolescents: a cross-sectional study in Kolkata, India.

BACKGROUND: Unhealthy eating and lack of exercise during adolescence culminated into earlier onset and increasing burden of atherosclerotic cardiovascular diseases (CVDs) worldwide. Among urban Indian adolescents, prevalence of these risk factors of CVD seemed to be high, but data regarding their pattern and predictors was limited. To address this dearth of information, a survey was conducted among urban adolescent school-students in Kolkata, a highly populated metro city in eastern India. METHODS: During January-June, 2014, 1755 students of 9th-grade were recruited through cluster (schools) random sampling. Informed consents from parents and assents from adolescents were collected. Information on socio-demographics, CVD-related knowledge and perception along with eating and exercise patterns were collected with an internally validated structured questionnaire. Descriptive and regression analyses were performed in SAS-9.3.2. RESULTS: Among 1652 participants (response rate = 94.1%), about 44% had poor overall knowledge about CVD, 24% perceived themselves as overweight and 60% considered their general health as good. Only 18% perceived their future CVD-risk and 29% were engaged in regular moderate-to-vigorous exercise. While 55% skipped meals regularly, 90% frequently consumed street-foods and 54% demonstrated overall poor eating habits. Males were more likely to engage in moderate-to-vigorous exercise [adjusted odds ratio (AOR) = 3.40(95% confidence interval = 2.55-4.54)] while students of higher SES were less likely [AOR = 0.59(0.37-0.94)]. Males and those having good CVD-related knowledge were more likely to exercise at least 1 h/day [AOR = 7.77(4.61-13.07) and 2.90(1.46-5.78) respectively]. Those who perceived their future CVD-risk, skipped meals more [2.04(1.28-3.25)] while Males skipped them less [AOR = 0.62(0.42-0.93)]. Subjects from middle class ate street-foods less frequently [AOR = 0.45(0.24-0.85)]. Relatively older students and those belonging to higher SES were less likely to demonstrate good eating habits [AOR = 0.70(0.56-0.89) and 0.23(0.11-0.47) respectively]. A large knowledge-practice gap was evident as students with good CVD-related knowledge were less likely to have good eating habits [AOR = 0.55(0.32-0.94)]. CONCLUSIONS: CVD-related knowledge as well as eating and exercise habits were quite poor among adolescent school-students of Kolkata. Additionally, there was a large knowledge-practice gap. Multi-component educational interventions targeting behavioral betterment seemed necessary for these adolescents to improve their CVD-related knowledge, along with appropriate translation of knowledge into exercise and eating practices to minimize future risk of CVDs.

Effects of protein-DNA complex formation on the intermolecular vibrational density of states of interfacial water.

Single-stranded DNAs (ss-DNAs) are formed as intermediates during DNA metabolic processes. ss-DNA binding (SSB) proteins specifically bind to the single-stranded segments of the DNA and protect it from being degraded. We have performed room temperature molecular dynamics simulations of the aqueous solution of two DNA binding K homology (KH) domains (KH3 and KH4) of the far upstream element (FUSE) binding protein (FBP) complexed with two ss-DNA oligomers. Efforts have been made to explore the influence of complex formation on low-frequency vibrational density of states of the surface water molecules. It is revealed that increased back scattering of water confined around the complexed structures leads to significant blue shifts of the band corresponding to the O···O···O bending or restricted transverse motions of water, the effect being more for the bridged water molecules. Importantly, it is demonstrated that the formation of such complexed structures of a similar type may often influence the transverse and longitudinal degrees of freedom of the surrounding water molecules in a nonuniform manner.

Exploring ion induced folding of a single-stranded DNA oligomer from molecular simulation studies.

One crucial issue in DNA hydration is the effect of salts on its conformational features. This has relevance in biology as cations present in the cellular environment shield the negative charges on the DNA backbone, thereby reducing the repulsive force between them. By screening the negative charges along the backbone, cations stabilize the folded structure of DNA. To study the effect of the added salt on single-stranded DNA (ss-DNA) conformations, we have performed room temperature molecular dynamics simulations of an aqueous solution containing the ss-DNA dodecamer with the 5'-CGCGAATTCGCG-3' sequence in the presence of 0.2, 0.5, and 0.8 M NaCl. Our calculations reveal that in the presence of the salt, the DNA molecule forms more collapsed coil-like conformations due to the screening of negative charges along the backbone. Additionally, we demonstrated that the formation of an octahedral inner-sphere complex by the strongly bound ion plays an important role in the stabilization of such folded conformation of DNA. Importantly, it is found that ion-DNA interactions can also explain the formation of non-sequential base stackings with longer lifetimes. Such non-sequential base stackings further stabilize the collapsed coil-like folded form of the DNA oligomer.

Thermodynamics of complex structures formed between single-stranded DNA oligomers and the KH domains of the far upstream element binding protein.

The noncovalent interaction between protein and DNA is responsible for regulating the genetic activities in living organisms. The most critical issue in this problem is to understand the underlying driving force for the formation and stability of the complex. To address this issue, we have performed atomistic molecular dynamics simulations of two DNA binding K homology (KH) domains (KH3 and KH4) of the far upstream element binding protein (FBP) complexed with two single-stranded DNA (ss-DNA) oligomers in aqueous media. Attempts have been made to calculate the individual components of the net entropy change for the complexation process by adopting suitable statistical mechanical approaches. Our calculations reveal that translational, rotational, and configurational entropy changes of the protein and the DNA components have unfavourable contributions for this protein-DNA association process and such entropy lost is compensated by the entropy gained due to the release of hydration layer water molecules. The free energy change corresponding to the association process has also been calculated using the Free Energy Perturbation (FEP) method. The free energy gain associated with the KH4-DNA complex formation has been found to be noticeably higher than that involving the formation of the KH3-DNA complex.

Arbitrarily Long Relativistic Bit Commitment.

We consider the recent relativistic bit commitment protocol introduced by Lunghi et al. [Phys. Rev. Lett. 115, 030502 (2015)] and present a new security analysis against classical attacks. In particular, while the initial complexity of the protocol scales double exponentially with the commitment time, our analysis shows that the correct dependence is only linear. This has dramatic implications in terms of implementation: in particular, the commitment time can easily be made arbitrarily long, by only requiring both parties to communicate classically and perform efficient classical computation.

Dynamics of water around the complex structures formed between the KH domains of far upstream element binding protein and single-stranded DNA molecules.

Single-stranded DNA (ss-DNA) binding proteins specifically bind to the single-stranded regions of the DNA and protect it from premature annealing, thereby stabilizing the DNA structure. We have carried out atomistic molecular dynamics simulations of the aqueous solutions of two DNA binding K homology (KH) domains (KH3 and KH4) of the far upstream element binding protein complexed with two short ss-DNA segments. Attempts have been made to explore the influence of the formation of such complex structures on the microscopic dynamics and hydrogen bond properties of the interfacial water molecules. It is found that the water molecules involved in bridging the ss-DNA segments and the protein domains form a highly constrained thin layer with extremely retarded mobility. These water molecules play important roles in freezing the conformational oscillations of the ss-DNA oligomers and thereby forming rigid complex structures. Further, it is demonstrated that the effect of complexation on the slow long-time relaxations of hydrogen bonds at the interface is correlated with hindered motions of the surrounding water molecules. Importantly, it is observed that the highly restricted motions of the water molecules bridging the protein and the DNA components in the complexed forms originate from more frequent hydrogen bond reformations.

Effect of temperature on the low-frequency vibrational spectrum and relative structuring of hydration water around a single-stranded DNA.

Molecular dynamics simulations of the single-stranded DNA oligomer (5'-CGCGAAT TCGCG-3') in aqueous solution have been carried out at different temperatures between 160 K and 300 K. The effects of temperature on the low-frequency vibrational spectrum and local structural arrangements of water molecules hydrating the DNA strand have been explored in detail. The low-frequency density of states distributions reveal that increasingly trapped transverse water motions play a dominant role in controlling the band corresponding to O⋯O⋯O bending or transverse oscillations of hydration water at supercooled temperatures. In addition, presence of a broad band around 260 (±20) cm(-1) under supercooled conditions indicates transformation from high density liquid-like structuring of hydration water at higher temperatures to that of a low density liquid at lower temperatures. It is found that long-range correlations between the supercooled hydration water molecules arise due to such local structural transition around the DNA oligomer.

Microscopic dynamics of water around unfolded structures of barstar at room temperature.

The breaking of the native structure of a protein and its influences on the dynamic response of the surrounding solvent is an important issue in protein folding. In this work, we have carried out atomistic molecular dynamics simulations to unfold the protein barstar at two different temperatures (400 K and 450 K). The two unfolded forms obtained at such high temperatures are further studied at room temperature to explore the effects of nonuniform unfolding of the protein secondary structures along two different pathways on the microscopic dynamical properties of the surface water molecules. It is demonstrated that though the structural transition of the protein in general results in less restricted water motions around its segments, but there are evidences of formation of new conformational motifs upon unfolding with increasingly confined environment around them, thereby resulting in further restricted water mobility in their hydration layers. Moreover, it is noticed that the effects of nonuniform unfolding of the protein segments on the relaxation times of the protein-water (PW) and the water-water (WW) hydrogen bonds are correlated with hindered hydration water motions. However, the kinetics of breaking and reformation of such hydrogen bonds are found to be influenced differently at the interface. It is observed that while the effects of unfolding on the PW hydrogen bond kinetics seem to be minimum, but the kinetics involving the WW hydrogen bonds around the protein segments exhibit noticeably heterogeneous characteristics. We believe that this is an important observation, which can provide valuable insights on the origin of heterogeneous influence of unfolding of a protein on the microscopic properties of its hydration water.

Molecular dynamics simulation of a single-stranded DNA with heterogeneous distribution of nucleobases in aqueous medium.

The DNA metabolic processes often involve single-stranded DNA (ss-DNA) molecules as important intermediates. In the absence of base complementarity, ss-DNAs are more flexible and interact strongly with water in aqueous media. Ss-DNA-water interactions are expected to control the conformational flexibility of the DNA strand, which in turn should influence the properties of the surrounding water molecules. We have performed room temperature molecular dynamics simulation of an aqueous solution containing the ss-DNA dodecamer, 5'-CGCGAATTCGCG-3'. The conformational flexibility of the DNA strand and the microscopic structure and ordering of water molecules around it have been explored. The simulation reveals transformation of the initial base-stacked form of the ss-DNA to a fluctuating collapsed coil-like conformation with the formation of a few non-sequentially stacked base pairs. A preliminary analysis shows further collapse of the DNA conformation in presence of additional salt (NaCl) due to screening of negative charges along the backbone by excess cations. Additionally, higher packing of water molecules within a short distance from the DNA strand is found to be associated with realignment of water molecules by breaking their regular tetrahedral ordering.

Interaction of Camptothecin with Model Cellular Membranes.

Accurate and efficient prediction of drug partitioning in model membranes is of significant interest to the pharmaceutical industry. Herein, we utilize advanced sampling methods, specifically, the adaptive biasing force methodology to calculate the potential of mean force for a model hydrophobic anticancer drug, camptothecin (CPT), across three model interfaces. We consider an octanol bilayer, a thick octanol/water interface, and a model 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)/water interface. We characterize the enthalpic and entropic contributions of the drug to the potential of mean force. We show that the rotational entropy of the drug is inversely related to the probability of hydrogen bond formation of the drug with the POPC membrane. In addition, in long-time microsecond simulations of a high concentration of CPT above the POPC membrane, we show that strong drug-drug aromatic interactions shift the spatial orientation of the drug with the membrane. Stacks of hydrophobic drugs form, allowing penetration of the drug just under the POPC head groups. These results imply that inhomogeneous membrane models need to take into account the effect of drug aggregation on the membrane environment.

Rational Coarse-Grained Molecular Dynamics Simulations of Supramolecular Anticancer Nanotubes.

Peptide self-assembly has been used to design an array of nanostructures that possess functional biomedical applications. Experimental studies have reported nanofilament and nanotube formation from peptide-based drug amphiphiles (DAs). These DAs have shown to possess an inherently high drug loading with a tunable release mechanism. Herein, we report rational coarse-grained molecular dynamics simulations of the self-assembly process and the structure and stability of preassembled nanotubes at longer timescales (µs). We find that aggregation between these DAs at the submicrosecond timescale is driven by directional aromatic interactions between the drugs. The drugs form a large and high-density nucleus that is stable throughout microsecond timescales. Simulations of nanotubes characterize the drug-drug stacking and find correlations at nanometer length scales. These simulations can inform the rational molecular design of drug amphiphiles.

Molecular Mechanism for the Role of the H2A and H2B Histone Tails in Nucleosome Repositioning.

The nucleosome core particle (NCP) is the basic packaging unit of DNA. Recently reported structures of the NCP suggest that the histone octamer undergoes conformational changes during the process of DNA translocation around the histone octamer. Herein, we demonstrate with long-time all-atomistic molecular dynamics simulations that the histone tails play a critical role in this nucleosome repositioning. We simulate the NCP at high salt concentrations, an order of magnitude higher than physiological conditions, to screen the electrostatic interactions. We find that the positively charged H2B tail collapses and complexes with the minor groove of nucleosomal DNA. Upon collapse of the tail, counterions are released. This promotes the formation of a ∼10 bp loop of nucleosomal DNA. The complexation of the tail increases the local flexibility of the DNA, as characterized by local force constants. Using normal mode analysis, we identify a "wave-like motion" of nucleosomal DNA. We perform umbrella sampling to characterize two possible pathways of the initial stages of unwrapping, symmetric and asymmetric. These results suggest that regulation of the histone tail interactions with nucleosomal DNA may play a critical role in nucleosomal dynamics by acting as a switch to determine the initial pathway of unwrapping.

Effect of Nucleotide State on the Protofilament Conformation of Tubulin Octamers.

At the molecular level, the dynamic instability (random growth and shrinkage) of the microtubule (MT) is driven by the nucleotide state (GTP vs GDP) in the ß subunit of the tubulin dimers at the MT cap. Here, we use large-scale molecular dynamics (MD) simulations and normal-mode analysis (NMA) to characterize the effect of a single GTP cap layer on tubulin octamers composed of two neighboring protofilaments (PFs). We utilize recently reported high-resolution structures of dynamic MTs to simulate a GDP octamer both with and without a single GTP cap layer. We perform multiple replicas of long-time atomistic MD simulations (3 replicas, 0.3 µs for each replica, 0.9 µs for each octamer system, and 1.8 µs total) of both octamers. We observe that a single GTP cap layer induces structural differences in neighboring PFs, finding that one PF possesses a gradual curvature, compared to the second PF which possesses a kinked conformation. This results in either curling or splaying between these PFs. We suggest that this is due to asymmetric strengths of longitudinal contacts between the two PFs. Furthermore, using NMA, we calculate mechanical properties of these octamer systems and find that octamer system with a single GTP cap layer possesses a lower flexural rigidity.