Optimized Collective Variable for Collapse Transition in Linear Hydrophobic Polymers: Importance of Hydration Water and End-to-End Distance.

Choosing an appropriate collective variable (CV) for any biomolecular process is a challenging task. Researchers are developing methods to solve this issue using a variety of methodologies, most recently using machine learning (ML) methods. In this work, we investigate the mechanism of collapse transition across various lengths of polymer systems through adaptively sampled multiple short trajectories utilizing the Time Lagged Independent Component Analysis (TICA) framework.

Modulation of the conformational landscape of the PDZ3 domain by perturbation on a distal non-canonical α3 helix: decoding the microscopic mechanism of allostery in the PDZ3 domain.

While allosteric signal transduction is crucial for protein signaling and regulation, the dynamic process of allosteric communication remains poorly understood. The third PDZ domain (PDZ stands for the common structural domain shared by the postsynaptic density protein (PSD95), Drosophila disc large tumor suppressor (DlgA), and zonula occludens-1 protein (ZO-1)) serves as a classic example of a single-domain allosteric protein, demonstrating a long-range coupling between the C-terminal α helix (known as the α3 helix) and ligand binding. A molecular level understanding of how the α3 helix modulates the ligand binding affinity of the PDZ3 domain is still lacking.

Accurate Prediction of Antifreeze Protein from Sequences through Natural Language Text Processing and Interpretable Machine Learning Approaches.

Antifreeze proteins (AFPs) bind to growing iceplanes owing to their structural complementarity nature, thereby inhibiting the ice-crystal growth by thermal hysteresis. Classification of AFPs from sequence is a difficult task due to their low sequence similarity, and therefore, the usual sequence similarity algorithms, like Blast and PSI-Blast, are not efficient. Here, a method combining -gram feature vectors and machine learning models to accelerate the identification of potential AFPs from sequences is proposed.

Supramolecular alternating copolymers with highly efficient fluorescence resonance energy transfer.

This article reports alternating supramolecular copolymerization of two naphthalene-diimide (NDI)-derived building blocks (NDI-1 and NDI-2) under thermodynamic control. Both monomers contain a central NDI chromophore, attached to a hydrocarbon-chain and a carboxylic-acid group. The NDI core in NDI-2 is symmetrically substituted with two butane-thiol groups, which makes it distinct from NDI-1.

Decoupling of Interactions between Model-Charged Peptides Reveals Key Factors Responsible for Liquid-Liquid Phase Separation.

Liquid-liquid phase separation (LLPS) by disordered proteins has been shown to govern biological processes and cause numerous diseases. Therefore, a deeper understanding of the interactions and their variation with external factors is key to modulating the LLPS behavior of different systems and protecting proteins from pathological aggregation. In this context, we have looked at interactions between similarly charged peptides to understand the molecular features that may drive or prevent condensate formation under various conditions.

Preferential Ordering and Organization of Hydration Water Favor Nucleation of Ice by Ice-Nucleating Proteins over Antifreeze Proteins.

Bacteria containing ice-nucleating proteins (INPs) evolved in nature to nucleate ice at the high sub-zero ambiance. The ability of the INPs to induce order in the hydration layer and their aggregation propensity appear to be key factors of their ice nucleation abilities. However, the mechanism of the process of ice nucleation by INPs is yet to be understood clearly.

Road-blocker HSP disease mutation disrupts pre-organization for ATP hydrolysis in kinesin through a second sphere control.

Kinesin motor proteins perform several essential cellular functions powered by the adenosine triphosphate (ATP) hydrolysis reaction. Several single-point mutations in the kinesin motor protein KIF5A have been implicated to hereditary spastic paraplegia disease (HSP), a lethal neurodegenerative disease in humans. In earlier studies, we have shown that a series of HSP-related mutations can impair the kinesin's long-distance displacement or processivity by modulating the order-disorder transition of the linker connecting the heads to the coiled coil.

Number of Hydrogen Bonds per Unit Solvent Accessible Surface Area: A Descriptor of Functional States of Proteins.

Proteins function close to native and near-native conformations. These states are evolutionarily selected to ensure the effect of mutations is minimized. The structural organization of a protein is hierarchical and modular, which reduces the dimensionality of the configurational space of the native states.

Real-time Observation of Macroscopic Helical Morphologies under Optical Microscope: A Curious Case of π-π Stacking Driven Molecular Self-assembly of an Organic Gelator Devoid of Hydrogen Bonding.

Supramolecular assemblies such as tubules/helix/double helix/helical tape etc. are usually submicron objects preventing direct observation under optical microscope. Chiral-pure form of these assemblies is important for potential applications.

Molecular Factors of Ice Growth Inhibition for Hyperactive and Globular Antifreeze Proteins: Insights from Molecular Dynamics Simulation.

The molecular mechanism behind the ice growth inhibition by antifreeze proteins (AFPs) is yet to be understood completely. Also, what physical parameters differentiate between the AFP and non-AFP are largely unknown. Thus, to get an atomistic overview of the differential antifreeze activities of different classes of AFPs, we have studied ice growth from different ice surfaces in the presence of a moderately active globular type III AFP and a hyperactive spruce budworm (sbw) AFP.

Identifying the Template for Oligomer to Fibril Conversion for Amyloid-β (1-42) Oligomers using Hamiltonian Replica Exchange Molecular Dynamics.

The toxicity of amyloid-β (Aβ) oligomers has been known to be higher compared to mature fibrils. Yet the presence of plaques in Alzheimer's disease patients indicates the significance of oligomer to fibril conversion for Aβ aggregates. In this study, we investigate Aβ oligomers having two to five peptide chains using extensive all-atom molecular dynamics simulations to identify the on- or off-pathway intermediates in fibril formation pathway.

Direct Participation of Solvent Molecules in the Formation of Supramolecular Polymers.

This article reports supramolecular polymerization of two bis-amide functionalized naphthalene-diimide (NDI) building blocks (NDI-L and NDI-C) in two solvents, namely n-heptane (Hep) and methylcyclohexane (MCH). NDI-L and NDI-C differ only by the peripheral hydrocarbon wedges, consisting of linear C7 chains or cyclic methylcyclohexane rings, respectively. UV/Vis and FTIR spectroscopy studies reveal distinct internal order and H-bonding pattern for NDI-L and NDI-C aggregates irrespective of the solvent system, indicating the dominant role of the intrinsic packing parameters of the individual building block, possibly influenced by the peripheral steric crowding.

Curious Case of MAD2 Protein: Diverse Folding Intermediates Leading to Alternate Native States.

Anfinsen's dogma postulates that for one sequence there will be only one unique structure that is necessary for the functioning of the protein. However, over the years there have been a number of departures from this postulate. As far as function is considered, there are growing examples of proteins that "moonlight", perform multiple unrelated functions.

Molecular Insight into the Effect of a Single-Nucleotide Polymorphic Variation on the Structure and Dynamics of Methionine Synthase Reductase and Its Association with Neural Tube Defects.

Neural tube defects (NTDs) are among the common and severe congenital malformations in neonates. According to a WHO report, nearly three lakh babies are affected per year worldwide by NTDs. Most studies revealed that folate deficiency is the key element to promote NTD with other oligogenic and multifactorial elements.

Kinetic and thermodynamic stability comparison for the fibrillar form of small amyloid-β(1-42) oligomers using scaled molecular dynamics.

Amyloid-β (Aβ) oligomers act as intermediates for several neurodegenerative disease-relevant fibril formations. However, gaining insight into the oligomer to fibril conversion process remains a challenge due to the transient nature of small Aβ. In this study, we probe the kinetic and thermodynamic stabilities of small Aβ(1-42) oligomers in fibrillar conformations to understand from what size these aggregates start forming stable fibrils.

Role of Calcium in Modulating the Conformational Landscape and Peptide Binding Induced Closing of Calmodulin.

Metal ions play an essential role in several cellular functions. Calcium is a ubiquitous regulator and is involved in numerous physiological processes. A class of proteins have evolved that sense calcium levels inside cells and act as effector molecules.

Mechanistic basis of propofol-induced disruption of kinesin processivity.

Propofol is a widely used general anesthetic to induce and maintain anesthesia, and its effects are thought to occur through impact on the ligand-gated channels including the GABA receptor. Propofol also interacts with a large number of proteins including molecular motors and inhibits kinesin processivity, resulting in significant decrease in the run length for conventional kinesin-1 and kinesin-2. However, the molecular mechanism by which propofol achieves this outcome is not known.

Computational modeling of dynein motor proteins at work.

Along with various experimental methods, a combination of theoretical and computational methods is essential to explore different length-scale and time-scale processes in the biological system. The functional mechanism of a dynein, an ATP-fueled motor protein, working in a multiprotein complex, involves a wide range of length/time-scale events. It generates mechanical force from chemical energy and moves on microtubules towards the minus end direction while performing a large number of biological processes including ciliary beating, intracellular material transport, and cell division.

Exploring the role of hydrophilic amino acids in unfolding of protein in aqueous ethanol solution.

Hydrophobic association is the key contributor behind the formation of well packed core of a protein which is often believed to be an important step for folding from an unfolded chain to its compact functional form. While most of the protein folding/unfolding studies have evaluated the changes in the hydrophobic interactions during chemical denaturation, the role of hydrophilic amino acids in such processes are not discussed in detail. Here we report the role of the hydrophilic amino acids behind ethanol induced unfolding of protein.

On the Correlation between Pair Hydrophobicity and Mixing Enthalpies in Water-Alcohol Binary Mixtures.

In this article, we have explored the extent of pair hydrophobicity in water-alcohol binary mixtures upon varying the chain length of the alcohol at several compositions. We have measured the pair hydrophobicity in water-methanol, water-propanol, and water-butanol mixtures. The pair hydrophobicity is measured by the depth of the first minimum (contact minimum) in the potential of mean force profile between a pair of neopentanes.

Structural insight into the effect of polymorphic variation on the functional dynamics of methionine synthase reductase: Implications in neural tube defects.

Neural tube defects (NTDs), one of the most common birth defects, are strongly associated with the variations of several single nucleotide polymorphisms (SNPs) in the MTRR gene. The gene codes a key enzyme that is involved in the rejuvenation of methionine synthase activity. An allelic variant of the protein leads to missense mutation at 49th position from isoleucine to methionine (I49M) is associated with higher disease prevalence in different populations.

Novel Mechanism of Cholesterol Transport by ABCA5 in Macrophages and Its Role in Dyslipidemia.

Cholesterol homeostasis results from a delicate interplay between influx and efflux of free cholesterol primarily mediated by ABCA1. Here we report downregulation of ABCA1 in hyper-cholesterol conditions in macrophages, which might be responsible for compromised reverse cholesterol transport and hyperlipidemia. Surprisingly, this is countered by the upregulation of a lesser known family member ABCA5 to maintain cholesterol efflux.

Deciphering the Role of the Non-ice-binding Surface in the Antifreeze Activity of Hyperactive Antifreeze Proteins.

Antifreeze proteins (AFPs) show thermal hysteresis through specific interaction with the ice crystal. Hyperactive AFPs interact with the ice surface through a threonine-rich motif present at their ice-binding surface (IBS). Ordering of water around the IBS was extensively investigated.

Intersubunit Assisted Folding of DNA Binding Domains in Dimeric Catabolite Activator Protein.

The abundance of protein dimers and multidomain proteins is a testimony to their importance in various cellular functions. Several mechanisms exist, explaining how they assemble. The energy landscape theory has shown that, irrespective of the mechanism followed, folding and binding of dimers and multidomain proteins are funneled processes.

Ionophore constructed from non-covalent assembly of a G-quadruplex and liponucleoside transports K-ion across biological membranes.

The selective transport of ions across cell membranes, controlled by membrane proteins, is critical for a living organism. DNA-based systems have emerged as promising artificial ion transporters. However, the development of stable and selective artificial ion transporters remains a formidable task.