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We have performed molecular dynamics (MD) simulation of the thermal denaturation of one protein and one peptide—ubiquitin and melittin. To identify the correlation in dynamics among various secondary structural fragments and also the individual contribution of different residues towards thermal unfolding, principal component analysis method was applied in order to give a new insight to protein dynamics by analyzing the contribution of coefficients of principal components. The cross-correlation matrix obtained from MD simulation trajectory provided important information regarding the anisotropy of backbone dynamics that leads to unfolding. Unfolding of ubiquitin was found to be a three-state process, while that of melittin, though smaller and mostly helical, is more complicated. [ABSTRACT FROM AUTHOR]

Cancer pathologies are associated with the unfolding and aggregation of most recurring mutations in the DNA Binding Domain (DBD) of p53 that coordinate the destabilization of protein. Substitution at the 175th codon with arginine to histidine (R175H, a mutation of large to small side-chain amino acid) destabilizes the DBD by 3 kcal/mol and triggers breasts, lung cancer, etc. Stabilizing the p53 mutant by small molecules offers an attractive drug-targeted anti-cancer therapy. The thiosemicarbazone (TSC) molecules NPC and DPT are known to act as zinc-metallochaperones to reactivate p53R175H. Here, a combination of LESMD simulations for 10 TSC conformations with a p53R175H receptor, single ligand-protein conformation MD, and ensemble docking with multiple p53R175H conformations observed during simulations is suggested to identify the potential binding site of the target protein in light of their importance for the direct TSC – p53R175H binding. NPC binds mutant R175H in the loop region L2-L3, forming pivotal hydrogen bonds with HIS175, pi‑sulfur bonds with TYR163, and pi-alkyl linkages with ARG174 and PRO190, all of which are contiguous to the zinc-binding native site on p53DBD. DPT, on the other hand, was primarily targeting alternative binding sites such as the loop-helix L1/H2 region and the S8 strand. The similar structural characteristics of TSC-bound p53R175H complexes with wild-type p53DBD are thought to be attributable to involved interactions that favour binding free energy contributions of TSC ligands. Our findings may be useful in the identification of novel pockets with druggable properties. [Display omitted] • We explored the binding pocket of Thiosemicarbazones on mutant p53R175H using locally enhanced sampling molecular dynamics. • The possible binding sites were taken for searching key interactions employing a single-conformation MD and ensemble docking. • NSC319726 (NPC) in particular is expected to stabilize p53R175H and compel it to keep its native-like form. • NPC interacts in the loop region L2-L3 of p53R175H which is contiguous to the zinc-binding native site on p53DBD. • The binding sites comprising the L1/H2 region and S8 strand were dominantly targeted by the NSC319725 (DPT) molecule. [ABSTRACT FROM AUTHOR]

[Display omitted] • We explored the binding pocket on the NTD of SARS-CoV-2 spike glycoprotein for GM1 using CG-MD simulations. • Two possible binding sites were discovered using two different starting orientations of NTD. • More compacted interaction was seen between GM1 and NTD orientation I than II providing higher restriction for GM1 mobility. • The results predict that the spike NTD receptor is likely to penetrate through the lipid bilayer membrane with orientation II. Coarse-grained molecular dynamics simulations of the lipid bilayer mixture of POPC and cholesterol were carried out in the presence and absence of ganglioside monosialo 1 (GM1) with N - terminal domain (NTD) of SARS-CoV-2 spike glycoprotein. The interactions of GM1 with two different NTD orientations were compared. NTD orientation I compactly bind GM1 predominantly through the sialic acid and the external galactose moieties providing more restriction to GM1 mobility whereas orientation II is more distributed on the lipid surface and due to the relaxed mobility of GM1 there, presumably, the NTD receptor penetrates more through the membrane. [ABSTRACT FROM AUTHOR]

Studies on the structure and dynamics of interfacial water, emphasizing on the properties of water near the surface of biomolecules, are well reported, but there is a lack of evidence on the behavior of water near a comparatively rough surface containing molecules with a bulky head group like GM1. In this report we comparatively analyze the structure and dynamics of water as a function of distance from the lipid head group in GM1 containing lipid bilayers, with the lipid bilayers where GM1 is not present. This approach effectively demonstrates the behavioral difference and hence delayed convergence from bound water to bulk water in the presence of GM1 compared to a relatively smooth surface. [ABSTRACT FROM AUTHOR]

Brain spectrin enjoys overall structural and sequence similarity with erythroid spectrin, but less is known about its function. We utilized the fluorescence properties of tryptophan residues to monitor their organization and dynamics in brain spectrin. Keeping in mind the functional relevance of hydrophobic binding sites in brain spectrin, we monitored the organization and dynamics of brain spectrin bound to PRODAN. Results from red edge excitation shift (REES) indicate that the organization of tryptophans in brain spectrin is maintained to a considerable extent even after denaturation. These results are supported by acrylamide quenching experiments. To the best of our knowledge, these results constitute the first report of the presence of residual structure in urea-denatured brain spectrin. We further show from REES and time-resolved emission spectra that PRODAN bound to brain spectrin is characterized by motional restriction. These results provide useful information on the differences between erythroid spectrin and brain spectrin. [ABSTRACT FROM AUTHOR]

An all-atom molecular dynamics simulation shows concentration-dependent like-charge ion pairing of the guanidinium ion in an aqueous solution of guanidinium chloride. We have observed two types of like-charge ion pairing for guanidinium ions, namely, stacked ion pairs and solvent-separated ion pairs. Interestingly, both of these like-charge ion-pair formations are dependent on the concentration of guanidinium chloride in water. The probability of stacked like-charge ion-pair formation decreases, whereas, the probability of solvent-separated like-charge pairing increases as the concentration of guanidinium chloride increases, which is shown from radial distribution functions and is confirmed from the energy calculations. Besides like-charge ion-pair formation, we also investigated guanidinium chloride induced changes in water structure. Hydrogen-bond analysis indicates that guanidinium chloride does not alter the strict-hydrogen-bonding patterns of water, whereas, it breaks the bend-hydrogen bond and the non-hydrogen-bonding patterns. Tetrahedral order, nearest neighbor orientation, and distance distribution of water molecules around a probe water molecule show the extent of water structure distortion. [ABSTRACT FROM AUTHOR]

Interactions of amyloid-β (Aβ) with neuronal membrane are associated with the progression of Alzheimer’s disease (AD). Ganglioside GM1 has been shown to promote the structural conversion of Aβ and increase the rate of peptide aggregation; but the exact nature of interaction driving theses processes remains to be explored. In this work, we have carried out atomistic-scale computer simulations (totaling 2.65 µs) to investigate the behavior of Aβ monomer and dimers in GM1-containing raft-like membrane. The oligosaccharide head-group of GM1 was observed to act as scaffold for Aβ-binding through sugar-specific interactions. Starting from the initial helical peptide conformation, a β-hairpin motif was formed at the C-terminus of the GM1-bound Aβ-monomer; that didn’t appear in absence of GM1 (both in fluid POPC and liquid-ordered cholesterol/POPC bilayers and also in aqueous medium) within the simulation time span. For Aβ-dimers, the β-structure was further enhanced by peptide-peptide interactions, which might influence the propensity of Aβ to aggregate into higher-ordered structures. The salt-bridges and inter-peptide hydrogen bonds were found to account for dimer stability. We observed spontaneous formation of intra-peptide D23-K28 salt-bridge and a turn at V24GSN27 region - long been accepted as characteristic structural-motifs for amyloid self-assembly. Altogether, our results provide atomistic details of Aβ-GM1 and Aβ-Aβ interactions and demonstrate their importance in the early-stages of GM1-mediated Aβ-oligomerisation on membrane surface. [ABSTRACT FROM AUTHOR]

Abstract: The binding of serum mannose-binding protein A (MBP-A) to high mannose N-linked glycoproteins, present on the surface of microorganism, activates the complement system. It is very important to explore the overall conformations of these ligands in the binding site of the MBP-A, which is very much dependent on the conformation of the manno-di-, tri- and the penta-saccharides that represent the component structures of these high-mannose type oligosaccharides. Herein, we report the possible conformations of α-(1→6)-linked dimannoside, benzyl-substituted trimannoside and core pentamannoside of the N-linked glycan in the binding site of MBP-A, with the help of molecular dynamics simulations. The results indicate that for all three ligands in addition to the non-reducing terminal mannose moiety the reducing moieties also interact with protein. Binding free energy calculations also indicate that the benzyl-substituted trisaccharide has higher affinity in comparison to the methyl substituted one. We have also found some conformers of the pentasaccharide, which have higher binding affinity than the monosaccharide. [Copyright &y& Elsevier]

Abstract: Herein, we report the intrinsic conformational preferences of α-d-Manp-(1→6)-α,β-d-Manp, (1) in the free state and as two (ASAI and ConA) lectin-bound forms. NMR spectroscopy and molecular dynamics techniques are used as 3D-structural determination tools. In free form disaccharide 1 displays a fair amount of conformational freedom, with one major (ϕ/ψ 95±30°/195±20°) and one minor (95±30°/70±20°) conformations around the glycosidic linkage and around the ω angle, both the gg and gt rotamers are almost equally populated. This is a first report of a three-dimensional structure of 1 bound with ASAI. Both lectins recognize a major ϕ/ψ 95±30°/200±30° conformer with the ligand showing more flexibility in the binding site of ConA. Comparison of the mode of binding of the two lectins explains the differences in observed specificities. [Copyright &y& Elsevier]

Abstract: Molecular dynamics simulations of 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) bilayer were carried out at two different cholesterol concentrations. The interactions of cholesterol with water oxygen, carbonyl oxygens and phosphate non-ester oxygens are compared. At higher cholesterol concentration the distribution of water and carbonyl oxygens around the cholesterol hydroxyl oxygen gets altered with a concomitant increase in cholesterol–cholesterol contacts. The change in hydrogen bonding of cholesterol hydroxyl group with lipid as well as water is observed. Higher cholesterol concentration induces restriction in the POPC as well as cholesterol dynamics. Formation of cholesterol rich and cholesterol deficient domains are clearly identified. [Copyright &y& Elsevier]

The legume lectins are widely used as a model system for studying protein–carbohydrate and protein–protein interactions. They exhibit a fascinating quaternary structure variation. Recently, it has become clear that lectins exist as oligomers. Soybean agglutinin is a tetrameric legume lectin, each of whose subunits are glycosylated. In the present study we explore the main origin for the stability of soybean agglutinin dimer. In order to understand the role of glycosylation on the dimeric interface, we have carried out normal (298K), high temperatures (380K, 500K) long explicit solvent molecular dynamics (MD) simulations and compared the structural and conformational changes between the glycosylated and non-glycosylated dimers. The study reveals that the high degree of stability at normal temperature is mostly contributed by interfacial ionic interactions (~200 kcal/mol) between polar residues like Lys, Arg, Asp, Thr, Ser, Asn and Gln (62%). It maintains its overall folded conformation due to high subunit interactions at the non-canonical interface. Mainly five important hydrogen bonds between C O of one β sheet of one subunit with the N-H of other β strand of the other subunit help to maintain the structural integrity. Ten inter subunit salt-bridge interactions between Arg 185–Asṕ192, Lys 163–Asṕ169, Asp 169–Lyś 163 and Asp 192–Arǵ 185 at non-canonical interface appear to be important to maintain the three dimensional structure of SBA dimer. Moreover, our simulation results revealed that increase in vibrational entropy could decrease the free energy and contribute to the glycan-induced stabilization by ~45 kcal/mol at normal temperature. [ABSTRACT FROM AUTHOR]

Aggregation of protein causes various diseases including Alzheimer's disease, Parkinson's disease, and type II diabetes. It was found that aggregation of protein depends on many factors like temperature, pH, salt type, salt concentration, ionic strength, protein concentration, co solutes. Here we have tried to capture the aggregation mechanism and pathway of hen egg white lysozyme using molecular dynamics simulations at two different temperatures; 300 K and 340 K. Along with the all atom simulations to get the atomistic details of aggregation mechanism, we have used coarse grained simulation with MARTINI force field to monitor the aggregation for longer duration. Our results suggest that due to the aggregation, changes in the conformation of lysozyme are more at 340 K than at 300 K. The change in the conformation of the lysozyme at 300 K is mainly due to aggregation where at 340 K change in conformation of lysozyme is due to both aggregation and temperature. Also, a more compact aggregated system is formed at 340 K. Image 1 • Conformation of lysozyme changes after the aggregation. • In case of at 300 K the little change of conformation of lysozyme is mainly due to aggregation. • Above the denaturation temperature of lysozyme more compact aggregates were formed. • Aggregation of lysozymes is not specific. [ABSTRACT FROM AUTHOR]

To perform specific functional activities, the majority of proteins should fold into their distinct three-dimensional conformations. However, the biologically active conformation of a protein is generally found to be marginally stable than the other conformations that the chain can adopt. How a protein finds its native conformation from its post-synthesis unfolded structure in a complex conformational landscape is the unsolved question that still drives the protein folding community. Here, we report the folding mechanism of a globular protein, ubiquitin, from its chemically denatured state using all-atom molecular dynamics simulations. From the kinetic analysis of the simulated trajectories we show that the folding process can be described by the hydrophobic collapse mechanism, initiated by the "dewetting transition", and subsequently assisted by the origination of an N-terminal folding nucleus, and finally supported by a native salt-bridge interaction between K11 and E34. We show that ubiquitin folds via an intermediate. Finally, we confirm the presence of "biological water" and explain its role to the folding process. Unlabelled Image • Drying transition assists hydrophobic collapse • Sequential folding leads to the formation of folding nucleus. • Native salt bridge interaction stabilizes the hydrophobic core. • Existence of residual secondary structure helps folding. • Slow folding of the dangling C-terminus delays the folding process. [ABSTRACT FROM AUTHOR]