Conformational Properties of Poly(A)-Binding Protein Complexed with Poly(A) RNA.

Microscopic understanding of protein-RNA interactions is important for different biological activities, such as RNA transport, translation, splicing, silencing, etc. Polyadenine (Poly(A)) binding proteins (PABPs) make up a class of regulatory proteins that play critical roles in protecting the poly(A) tails of cellular mRNAs from nuclease degradation. In this work, we performed molecular dynamics simulations to investigate the conformational modifications of human PABP protein and poly(A) RNA that occur during complexation. It is demonstrated that the intermediate linker domain of the protein transforms from a disordered coil-like structure to a helical form during the recognition process, leading to the formation of the complex. On the other hand, disordered collapsed coil-like RNA on complexation has been found to transform into a rigid extended conformation. Importantly, the binding free energy calculation showed that the thermodynamic stability of the complex is primarily guided by favorable hydrophobic interactions between the protein and the RNA.

Ice Recrystallization Unveils the Binding Mechanism Operating at a Diffused Interface.

Recrystallization of ice is a natural phenomenon that causes adverse effects in cryopreservation, agriculture, and in frozen food industry. It has long been recognized that ice recrystallization occurs through the Ostwald ripening and accretion processes. However, neither of these processes has been explored in microscopic detail by state-of-the-art experimental techniques. We carried out atomistic molecular dynamics (MD) simulations to explore ice recrystallization through the accretion process. Attempts have been made to elucidate the binding mechanism that is operating at the diffused ice-water interface. It is demonstrated that two ice crystals spontaneously recognize each other and bind together to form a large crystal in liquid water, resulting in ice recrystallization by accretion. Interestingly, the study reveals that the binding occurs due to the freezing of the interfacial water layer present between the two ice planes, even at a temperature above the melting point of the ice crystal. The synergistically enhanced ordering effect of two ice surfaces on the interfacial water leads to such freezing occurring during the binding process. However, proper crystallographic alignment is not necessarily required for the binding of the two crystals. Simulations have also been carried out to study the binding between an ice crystal and the model ice-binding surface (IBS) of an antifreeze protein above the melting point of the ice crystal. It is found that such binding at the IBS is accompanied by freezing of the interfacial water. This establishes that the synergetic ordering-driven freezing of interfacial water is a common binding mechanism at the diffused surfaces of ice crystals. We believe that this mechanism will provide a microscopic understanding of the process of recrystallization inhibition and thus help in designing suitable materials for potent applications in recrystallization inhibition.

Conformational Properties of Aß Peptide Oligomers in Aqueous Ionic Liquid Solution: Insights from Molecular Simulation Studies.

Alzheimer's disease is a progressive irreversible neurological disorder with abnormal extracellular deposition of amyloid ß (Aß) peptides in the brain. We have carried out atomistic molecular dynamics simulations to investigate the size-dependent conformational properties of aggregated Aß oligomers of different orders, namely, pentamer [O(5)], decamer [O(10)], and hexadecamer [O(16)] in aqueous solutions containing the ionic liquid (IL) 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF4]). The calculations revealed reduced peptide conformational fluctuations in O(5) and O(10) in the presence of the IL. In contrast, the higher order oligomer [O(16)] has been found to exhibit greater structural distortion due to enhanced flexibilities of its peptide units in the presence of the IL. Based on the distributions of the solvent (water) and the cosolvent (IL) components, it is demonstrated that exchange of water by the IL ion pairs at the exterior surface of the oligomers primarily occurs beyond the first layer of surface-bound water molecules. Importantly, a reduced number of relatively weaker peptide salt bridges have been found in O(16) in binary water-IL solution as compared to the other two smaller-sized oligomers [O(5) and O(10)]. Such differential influence of the IL on peptide salt bridges results in less favorable binding free energies of peptide monomers to O(16), which leads to its greater structural distortion and reduced stability compared to those of O(5) and O(10).

Counteraction Effects of Ammonium-Based Ionic Liquids on Urea-Induced Denaturation of α-Lactalbumin: A Comprehensive Molecular Simulation Study.

Ionic liquids (ILs) are known to stabilize protein conformations in aqueous medium. Importantly, ILs can also act as refolding additives in urea-driven denaturation of proteins. However, despite the importance of the problem, detailed microscopic understanding of the counteraction effects of ILs on urea-induced protein denaturation remains elusive. In this work, atomistic molecular dynamics (MD) simulations of the protein α-lactalbumin have been carried out in pure aqueous medium, in 8 M binary urea-water solution and in ternary urea-IL-water solutions containing ammonium-based ethyl ammonium acetate (EAA) as the IL at different concentrations (1-4 M). Attempts have been made to quantify detailed molecular-level understanding of the origin behind the counteraction effects of the IL on urea-induced partial unfolding of the protein. The calculations revealed significant conformational changes of the protein with multiple free energy minima due to its partial unfolding in binary urea-water solution. The counteraction effect of the IL was evident from the enhanced structural rigidity of the protein with propensity to transform into a single native free energy minimum state in ternary urea-IL-water solutions. Such an effect has been found to be associated with preferential direct binding of the IL components with the protein and simultaneous expulsion of urea from the interface, thereby providing additional stabilization of the protein in ternary solutions. Most importantly, modified rearrangement of the hydrogen bond network at the interface due to the formation of stronger protein-cation (PC) and protein-anion (PA) hydrogen bonds by breaking relatively weaker protein-urea (PU) and protein-water (PW) hydrogen bonds has been recognized as the microscopic origin behind the counteraction effects of EAA on urea-induced partial unfolding of the protein.

Exploring the Heterogeneous Dynamical Environment at the Interface of Aß42 Peptide in Aqueous Ionic Liquid Solution.

In this study, we have investigated the heterogeneous dynamical environment around an ensemble of full-length amyloid-ß (Aß42) peptide monomers in binary aqueous solution containing the ionic liquid (IL) 1-butyl-3-methylimidazolium tetrafluoroborate [BMIM][BF4] as a co-solvent. Atomistic molecular dynamics (MD) simulations have been employed with the aim of understanding the effect of the IL on the distribution of water molecules and IL components around distinct segments of the peptide. As compared to pure aqueous medium, locally heterogeneous restricted water motions at the interface have been spotted in the presence of the IL. Our calculations revealed faster diffusion of water molecules hydrating hydrophilic segments (N-term and turn) as opposed to that around hydrophobic segments (hp1, hp2, and C-term). The extent of non-uniform restriction on the center-of-mass motions as well as the reorientation of water molecules and IL ions have been similarly affected in the binary IL-water solution. The effects of IL on the formation of hydrogen bond networks have been evident from the longer hydrogen bond relaxation time scales of peptide-water, with only a small fraction of peptide-anion hydrogen bonds contributing to the structural relaxation. Due to the size and shape factors, the increasingly sluggish dynamics of the IL components in the solvation shell can be attributed to a longer time scale for the onset of maximum dynamic heterogeneity. Interestingly, the water molecules around the polar segments of the peptide take longer to attain dynamic heterogeneity, which intensifies in the presence of IL. These calculations clearly suggest that electrostatic interaction plays a crucial role in water-mediated peptide-IL interaction, thereby shielding the surface from hydrophobic collapse and preventing possible further growth of the monomers into fibrils at higher peptide concentrations.

Microscopic Understanding of the Conformational Stability of the Aggregated Nonamyloid ß Components of α-Synuclein.

Self-association of α-synuclein peptides into oligomeric species and ordered amyloid fibrils is associated with Parkinson's disease, a progressive neurodegenerative disorder. In particular, the peptide domain formed between the residues Glu-61 (or E61) and Val-95 (or V95) of α-synuclein, typically termed the "nonamyloid ß component" (NAC), is known to play critical roles in forming aggregated structures. In this work, we have employed molecular dynamics simulations to explore the conformational properties and relative stabilities of aggregated protofilaments of different orders, namely, tetramer (P(4)), hexamer (P(6)), octamer (P(8)), decamer (P(10)), dodecamer (P(12)), and tetradecamer (P(14)), formed by the NAC domains of α-synuclein. Besides, center-of-mass pulling and umbrella sampling simulation methods have also been employed to characterize the mechanistic pathway of peptide association/dissociation and the corresponding free energy profiles. Structural analysis showed that the disordered C-terminal loop and the central core regions of the peptide units lead to more flexible and distorted structures of the lower order protofilaments (P(4) and P(6)) as compared to the higher order ones. Interestingly, our calculation shows the presence of multiple distinctly populated conformational states for the lower order protofilament P(4), which may drive the oligomerization process along multiple pathways to form different polymorphic α-synuclein fibrillar structures. It is further observed that the nonpolar interaction between the peptides and the corresponding nonpolar solvation free energy play a dominant role in stabilizing the aggregated protofilaments. Importantly, our result showed that reduced cooperativity during the binding of a peptide unit beyond a critical size of the protofilament (P(12)) leads to less favorable binding free energy of a peptide.

Impact of an Ionic Liquid on Amino Acid Side Chains: A Perspective from Molecular Simulation Studies.

Ionic liquids (ILs) are known to modify the structural stability of proteins. The modification of the protein conformation is associated with the accumulation of ILs around the amino acid (AA) side chains and the nature of interactions between them. To understand the microscopic picture of the structural arrangements of ILs around the AA side chains, room temperature molecular dynamics (MD) simulations have been carried out in this work with a series of hydrophobic, polar and charged AAs in aqueous solutions containing the IL 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF4]) at 2 M concentration. The calculations revealed distinctly nonuniform distribution of the IL components around different AAs. In particular, it is demonstrated that the BMIM+ cations preferentially interact with the aromatic AAs through favorable stacking interactions between the cation imidazolium head groups and the aromatic AA side chains. This results in preferential parallel alignments and enhanced population of the cations around the aromatic AAs. The potential of mean force (PMF) calculations revealed that such favorable stacking interactions provide greater stability to the contact pairs (CPs) formed between the aromatic AAs and the IL cations as compared to the other AAs. It is further quantified that for most of the AAs (except the cationic ones), a favorable enthalpy contribution more than compensates for the entropy cost to form stable CPs with the IL cations. These findings are likely to provide valuable fundamental information toward understanding the effects of ILs on protein conformational stability.

Elucidating the Sluggish Water Dynamics at the Ice-Binding Surface of the Hyperactive Tenebrio molitor Antifreeze Protein.

Quasi-ice-like hydration waters on the ice-binding surface (IBS) of an antifreeze protein (AFP) commonly exhibit sluggish dynamics especially at low temperatures. In this work, we have analyzed molecular dynamics (MD) simulation trajectories at two different temperatures for Tenebrio molitor antifreeze protein (TmAFP) to explore whether the unique quasi-ice-like structuring of hydration water has any impact on making their dynamics slower on the IBS of the protein. Our calculation reveals that, as translational dynamics is coupled with the conformational fluctuations, hydration water on the IBS exhibits sluggish translational motion due to reduced flexibility of the IBS compared to that on the non-ice-binding surface (NIBS) of the protein. Interestingly, it is noticed that rotational motion of hydration water is not coupled with the conformational fluctuations of the surfaces. In that case, structural relaxations of the protein-water (PW) and water-water (WW) hydrogen bonds compete with each other to make the rotational dynamics of hydration water around the IBS either faster or slower with respect to those around the NIBS. At low temperature, the slower structural relaxation of water-water hydrogen bonds dominates and imparts sluggish rotational motion of the hydration water on the IBS of the protein. The slower structural relaxation of water-water hydrogen bonds and hence the retarded rotational dynamics, despite the weak short-lived PW hydrogen bonds on the IBS, is clearly a manifestation of the rigid quasi-ice-like structure of the hydration shell on that surface.

In Silico Studies to Predict the Role of Solvent in Guiding the Conformations of Intrinsically Disordered Peptides and Their Aggregated Protofilaments.

The formation of amyloids due to the self-assembly of intrinsically disordered proteins or peptides is a hallmark for different neurodegenerative diseases. For example, amyloids formed by the amyloid beta (Aß) peptides are responsible for the most devastating neuropathological disease, namely, Alzheimer's disease, while aggregation of α-synuclein peptides causes the etiology of another neuropathological disease, Parkinson's disease. Characterization of the intermediates and the final amyloid formed during the aggregation process is, therefore, crucial for microscopic understanding of the origin behind such diseases, as well as for the development of proper therapeutics to combat those. However, most of the research activities reported in this area have been directed toward examining the early stages of the aggregation process, including probing the conformational characteristics of the responsible protein/peptide in the monomeric state or in small oligomeric forms. This is because the small soluble oligomers have been found to be more deleterious than the final insoluble amyloids. This review discusses some of the recent findings obtained from our simulation studies on Aß and α-synuclein monomers and small preformed Aß aggregates. A molecular-level insight of the aggregation process with a special emphasis on the role of water in inducing the aggregation process has been provided.

Exploring the Dynamic Heterogeneity at the Interface of a Protein in Aqueous Ionic Liquid Solutions.

Room temperature molecular dynamics (MD) simulations of the globular protein α-lactalbumin in aqueous solutions containing BMIM (1-butyl-3-methylimidazolium) based ionic liquids (ILs) with a series of Hofmeister anions have been carried out. In particular, effects of anions of different shapes/sizes and hydrophobic/hydrophilic characters, namely, thiocyanate (SCN-), dicyanamide (DCA-), methyl sulfate (MS-), triflate (TFO-), and bis(trifluoromethane) sulfonimide (TF2N-) on the heterogeneous dynamic environment at the interface around the protein have been explored. The calculations revealed exchange of population between water and IL cation-anion components beyond the first layer of bound water molecules at the protein surface. Further, increasingly restricted diffusivity of the IL components and water around the protein has been found to be associated with a longer time scale for the onset of dynamic heterogeneity at the interface. Restricted diffusivity of water molecules at the interface in the presence of the ILs has been found to be correlated with the longer time scale of structural relaxations of protein-water hydrogen bonds at the interface. More importantly, the time scale associated with the reorientations of the anions has been found to be anticorrelated with their translational diffusivity, with the effect being more at the interface as compared to the bulk IL solutions. It is demonstrated that the nonuniform ability of the anions to form hydrogen bonds with water due to their differential shapes and hydrophilic characters is the origin of such anticorrelation.

Exploring Heterogeneous Dynamical Environment around an Ensemble of Aß42 Peptide Monomer Conformations.

Exploring the conformational properties of amyloid ß (Aß) peptides and the role of solvent (water) in guiding the dynamical environment at their interfaces is crucial for microscopic understanding of Aß misfolding, which is involved in causing the most common neurodegenerative disorder, i.e., Alzheimer's disease. While numerous studies in the past have emphasized examining the conformational states of Aß peptides, the role of water has not received much attention. Here, we have performed all-atom molecular dynamics simulations of several full-length Aß42 peptide monomers with different initial configurations. Our efforts are directed toward probing the origin of the heterogeneous dynamics of water around various segments of the Aß peptide, identified as the two terminal segments (N-term and C-term) and the two hydrophobic segments (hp1 and hp2), along with the central turn region interconnecting hp1 and hp2. Our results revealed that water hydrating hp1, hp2, and turn (nonterminal segments) and C-term segments exhibit nonuniformly restricted translational as well as rotational motions. The degree of such restriction has been found to be correlated with the hydrogen bond relaxation time scales at the interface. Importantly, it is revealed that the water molecules around hp1 and, to some extent, around hp2, form relatively rigid hydration layers, compared to that around the other segments. Such rigid hydration layers arise due to relatively more solid-like caging motions resulting in relatively lesser hydration entropy. As hp1 and hp2 have been demonstrated to play a central role in Aß aggregation, we believe that distinct water dynamics in the vicinity of these two segments, as outlined in this study, can provide vital information in understanding the early stages of the onset of the aggregation process of such peptides at higher concentration that can further aid toward advances in AD therapeutics.

Dynamic Heterogeneity at the Interface of an Intrinsically Disordered Peptide.

It is believed that water around an intrinsically disordered protein or peptide (IDP) in an aqueous environment plays an important role in guiding its conformational properties and aggregation behavior. However, despite its importance, only a handful of studies exploring the correlation between the conformational motions of an IDP and the microscopic properties of water at its surface are reported. Attempts have been made in this work to study the dynamic properties of water present in the vicinity of α-synuclein, an IDP associated with Parkinson's disease (PD). Room temperature molecular dynamics (MD) simulations of eight α-synuclein1-95 peptides with a wide range of initial conformations have been carried out in aqueous media. The calculations revealed that due to solid-like caging motions, the translational and rotational mobility of water molecules near the surfaces of the peptide repeat unit segments R1 to R7 are significantly restricted. A small degree of dynamic heterogeneity in the hydration environment around the repeat units has been observed with water near the hydrophobic R6 unit exhibiting relatively more restricted diffusivity. The time scales involving the overall structural relaxations of peptide-water and water-water hydrogen bonds near the peptide have been found to be correlated with the time scale of diffusion of the interfacial water molecules. We believe that the relatively more hindered dynamic environment near R6 can help create water-mediated contacts centered around R6 between peptide monomers at a higher concentration, thereby enhancing the early stages of peptide aggregation.

Importance of Solvent in Guiding the Conformational Properties of an Intrinsically Disordered Peptide.

Aggregated form of α-synuclein in the brain has been found to be the major component of Lewy bodies that are hallmarks of Parkinson's disease (PD), the second most devastating neurodegenerative disorder. We have carried out room-temperature all-atom molecular dynamics (MD) simulations of an ensemble of widely different α-synuclein1-95 peptide monomer conformations in aqueous solution. Attempts have been made to obtain a generic understanding of the local conformational motions of different repeat unit segments, namely R1-R7, of the peptide and the correlated properties of the solvent at the interface. The analyses revealed relatively greater rigidity of the hydrophobic R6 unit as compared to the other repeat units of the peptide. Besides, water molecules around R6 have been found to be less structured and weakly interacting with the peptide. These are important observations as the R6 unit with reduced conformational motions can act as the nucleation site for the aggregation process, while less structured weakly interacting water around it can become displaced easily, thereby facilitating the hydrophobic collapse of the peptide monomers and their association during the nucleation phase at higher concentrations. In addition, we demonstrated presence of doubly coordinated highly ordered as well as triply coordinated relatively disordered water molecules at the interface. We believe that while the ordered water molecules can favor water-mediated interactions between different peptide monomers, the randomly ordered ones on the other hand are likely to be expelled easily from the interface, thereby facilitating direct peptide-peptide interactions during the aggregation process.

Contrasting Effects of Ionic Liquids of Varying Degree of Hydrophilicity on the Conformational and Interfacial Properties of a Globular Protein.

Ionic liquids (ILs), depending on their cation-anion combinations, are known to influence the conformational properties and activities of proteins in a nonuniform manner. To obtain microscopic understanding of such influence, it is important to characterize protein-IL interactions and explore the modified solvation environment around the protein. In this work, molecular dynamics (MD) simulations of the globular protein α-lactalbumin have been carried out in aqueous IL solutions containing 1-butyl-3-methylimidazolium cations (BMIM+) in combination with a series of anions with varying degree of hydrophilicity, namely, hexafluorophosphate (PF6-), ethyl sulfate (ETS-), acetate (OAc-), chloride (Cl-), dicyanamide (DCA-), and nitrate (NO3-) . The calculations revealed that ILs with hydrophobic and hydrophilic anions have contrasting influence on conformational flexibility of the protein. It is further observed that the BMIM+ cations exhibit site-specific orientations at the interface depending on the hydrophilicity of the anion component. Most importantly, the results demonstrated enhanced propensity of hydrophilic ILs to replace relatively weaker protein-water hydrogen bonds by stronger protein-IL hydrogen bonds at the protein surface as compared to the hydrophobic ILs. Such breaking of protein-water hydrogen bonds at a greater extent leads to greater loss of water hydrating the protein in the presence of hydrophilic ILs, thereby reducing the protein's stability.

Microscopic Understanding of the Effect of Ionic Liquid on Protein from Molecular Simulation Studies.

We have performed molecular dynamics (MD) simulations of the protein α-lactalbumin in aqueous solution containing the ionic liquid (IL) 1-butyl-3-methyl imidazolium tetrafluoroborate ([BMIM][BF4]) as the cosolvent at different concentrations. Attempts have been made to obtain quantitative understanding of the effects of the IL on the conformational features of the protein as well as the distributions of the IL and water around it. The calculations revealed enhanced rigidity of the protein with reduced conformational fluctuations and increasingly correlated local motions in the presence of the IL. Nonuniform relative population of the BMIM+ and BF4- ions at the protein surface with respect to that in the bulk solution has been observed. It is demonstrated that exchange of water by the IL around the protein results in rearrangement of the hydrogen bond network at the interface with breaking of protein-water hydrogen bonds and formation of protein-IL hydrogen bonds. Importantly, it is found that the protein forms increased number of stronger salt bridges in the presence of IL. This shows that the formation of a greater number of such stronger salt bridges is the origin behind the enhanced rigidity of the protein in the presence of the IL.

Heterogeneous Dynamical Environment at the Interface of a Protein-DNA Complex.

Binding between protein and DNA is an essential process to regulate different biological activities. Two puzzling questions in protein-DNA recognition are (i) how the protein's binding domain identifies the DNA sequence in an aqueous solution and (ii) how the formation of the complex alters the dynamical environment around it. In this work, we present results obtained from molecular dynamics simulations of the N-terminal α-helical domain of the λ-repressor protein (in dimeric form) bound to the corresponding operator DNA. Effects of formation of the complex in modifying the microscopic dynamics of water as well as the kinetics of hydrogen bonds at the interface have been explored. Locally heterogeneous restricted water motions at the complex interface have been observed, the extent of restriction being more significant around the directly bound residues of the protein and the DNA. In particular, the calculation revealed the existence of significantly constrained motionally restricted water layer that can form either bridges around the directly bound residues of the protein and DNA or are engaged in forming water-mediated contacts between a fraction of the unbound residues. More importantly, it is observed that the restricted water motion around the complex is correlated with the hydrogen bond relaxation time scale at the interface. It is further demonstrated that the kinetics of water-water hydrogen bonds involving the bridged water are influenced more due to complex formation.

Flexibility of the Binding Regions of a Protein-DNA Complex and the Structure and Ordering of Interfacial Water.

Noncovalent interactions between protein and DNA are important to comprehend different biological activities in living organisms. One important issue is how the protein identifies the target DNA and the influence of the resulting protein-DNA complex on the hydration environment around it. In this study, we have carried out atomistic molecular dynamics simulations of the protein-DNA complex formed by the dimeric form of the α-helical N-terminal domain of the λ-repressor protein with its operator DNA. Local heterogeneous flexibilities of the residues of the protein and the DNA components that are involved in binding and the microscopic structure and ordering of water around those have been investigated in detail. The calculations revealed concurrent existence of highly ordered as well as disordered water molecules at the interface. It is found that a fraction of doubly coordinated water molecules exhibit high degree of ordering at the interface, while the randomly oriented ones are coordinated with three water molecules. The effect has been found to be more around the protein and DNA residues that are in contact in the complexed state. We believe that such highly ordered two-coordinated water molecules are likely to act as an adhesive to facilitate the formation of a protein-DNA complex and maintain its structural stability.

Intermolecular Dynamics of Water: Suitability of Reactive Interatomic Potential.

Reactive interatomic potentials for water have been developed by researchers based on their ability of bond breaking and formation, which have numerous advantages and applications in different fields. The question that is being addressed in this work is whether these reactive interatomic potentials properly account for the intermolecular dynamics of water that includes both hydrogen bonding as well as librational motions. It should be noted that breaking and reformation of hydrogen bonds occur prior to covalent bond breaking of water molecules (which requires a significant amount of energy), which has numerous applications in absorption as well as solvation problems. Based on correlations with experimental observations, it has been demonstrated that the current forms of the reactive potentials perform poorly in comparison to other well-established empirical interatomic potential models of water, such as TIP4P/2005f, with regard to the intermolecular dynamics of water. Translational and rotational diffusivities, power spectra, and hydrogen-bond lifetime analyses are carried out and compared to available experimental data as well as those obtained from TIP4P/2005f models to arrive at such conclusions.

Effects of Metal Ions on Aß42 Peptide Conformations from Molecular Simulation Studies.

In this study, we investigate the conformational characteristics of full-length Aß42 peptide monomers in the presence of Na+ and Zn2+ metal ions using atomistic molecular dynamics (MD) simulations with an aim to explore the possible driving forces behind enhanced aggregation rates of the peptides in the presence of salts. The calculations reveal that the presence of metal ions shifts the conformational equilibrium more toward the compact ordered Aß structures. Such compact ordered structures stabilized by distant nonlocal contacts between two crucial hydrophobic segments, hp1 and hp2, primarily through two important hydrophobic aromatic residues, Phe-19 and Phe-20, are expected to trigger the aggregation process at a faster rate by populating and stabilizing the aggregation prone structures. Formation of a significant number of such distant contacts in the presence of Na+ ions has also been found to result in breaking of the N-terminal helix. On the contrary, binding of Zn2+ ion to Aß peptide is highly specific, which stabilizes the N-terminal helix instead of breaking it. This explains why the aggregation rate of Aß peptides is higher in the presence of divalent Zn2+ ions than monovalent Na+ ions. Relatively higher overall stability of the most populated Aß peptide monomers in the presence of Zn2+ ions has been found to be associated with specific Zn2+-Aß binding and significant free energy gain.

Role of Polar and Nonpolar Groups in the Activity of Antifreeze Proteins: A Molecular Dynamics Simulation Study.

Molecular dynamics simulations have been carried out separately with the hyperactive Tenebrio molitor antifreeze protein ( TmAFP) and with its nonactive mutant at 300 K to elucidate the role of polar and nonpolar groups in the activities of antifreeze proteins (AFPs). Simulation results reveal that both polar and nonpolar groups contribute to develop the required quasi-ice-like hydration layer on the ice-binding surface (IBS) of an AFP for binding onto ice. Nonpolar groups on the IBS induce the formation of locally ordered icelike low-density waters in the hydration layer through hydrophobic interactions, and polar groups of the surface integrate these waters into a quasi-ice-like layered structure through hydrogen-bonding interactions. These contributions of polar and nonpolar groups apparently contradict the behavior of winter flounder antifreeze protein (wfAFP) mutants possibly due to switching of IBS of wfAFP upon mutation of threonine residues with valine residues.