Insulin is a peptide hormone known for chiefly regulating glucose level in blood among several other metabolic processes. Insulin remains the most effective drug for treating diabetes mellitus. Insulin is synthesized in the pancreatic β-cells where it exists in a compact hexameric architecture although its biologically active form is monomeric. Insulin exhibits a sequence of conformational variations during the transition from the hexamer state to its biologically-active monomer state. The structural transitions and the mechanism of action of insulin have been investigated using several experimental and computational methods. This review primarily highlights the contributions of molecular dynamics (MD) simulations in elucidating the atomic-level details of conformational dynamics in insulin, where the structure of the hormone has been probed as a monomer, dimer, and hexamer. The effect of solvent, pH, temperature, and pressure have been probed at the microscopic scale. Given the focus of this review on the structure of the hormone, simulation studies involving interactions between the hormone and its receptor are only briefly highlighted, and studies on other related peptides (e.g., insulin-like growth factors) are not discussed. However, the review highlights conformational dynamics underlying the activities of reported insulin analogs and mimetics. The future prospects for computational methods in developing promising synthetic insulin analogs are also briefly highlighted.

The crucial residues of hBaxBH3 peptide for interaction with hBcl-B, an anti-apoptotic protein, were identified using molecular docking studies on the polypeptides and temperature-specific molecular dynamic simulations performed for the protein-peptide complex at near-physiological conditions (pH 7.0, 1 atmospheric pressure and 0.1 M NaCl). The data from the methods were examined by a 'strong residue contacts' filter strategy and the data analyses of the former and latter methods identified 10 (Q52, K57, S60, L63, K64, R65, G67, D68, D71 & S72) and 3 (S60, E61 & K64) crucial residues of the hBaxBH3 peptide for interacting with the protein, respectively. We have herein demonstrated that BH3-chemical mimetics screened using the pharmacophoric residues of hBaxBH3 obtained from the 'peptidodynmimetic method' were superior in terms of ligand efficiencies, bioavailability and pharmacokinetic properties vis-à-vis that of small molecule BH3-mimetics retrieved using the conventional 'peptidomimetic method'. The unique advantages of the 'peptidodynmimetic method' to identify efficient BH3-mimetics for modulating interfaces (composed of a large number of amino acids) of other anti-apoptotic proteins-BH3-only peptides have also been discussed in detail.

Cardiotoxins (CTXs) belonging to the three-finger toxin superfamily of snake venoms are one of principal toxic components and the protein toxins exhibit membrane lytic activities when the venoms are injected into victims. In the present study, complex formations between CTX VI (a P-type CTX from Naja atra) and CTX1 (an S-type CTX from Naja naja) on zwitterionic POPC bilayers (a major lipid component of cell membranes) have been studied in near physiological conditions for a total dynamic time scale of 1.35 μs using all-atom molecular dynamics (MD) simulations. Comprehensive analyses of the MD data revealed that residues such as Leu1, Lys2, Tyr11, Lys31, Asp57 and Arg58 of CTX VI, and Ala16, Lys30 and Arg58 of CTX1 were crucial for establishing interactions with the POPC bilayer. Moreover, loop I, along with globular head and loop II of CTX VI, and loop II of CTX1 were found to be the structural regions chiefly governing complex formation of the respective proteins with POPC. Rationalizations for the differential binding modes of CTXs and implications of the findings for designing small molecular inhibitors to the toxins are also discussed. Graphical Abstract Binding modes of a P-type CTX and an S-type CTX towards the POPC bilayer.

Significant secondary structural changes in the SARS-CoV-2 RBD upon single (N501Y), double (E484Q and L452R) and triple (N501Y, E484Q, and L452R) mutations lead to different binding affinities of the variants to the human ACE2 receptor.

In experimental research-driven biomaterials science, the influence of different material properties (elastic stiffness, surface energy, etc.) and, to a relatively lesser extent, biophysical stimulation (electric/magnetic) on cell−material interactions has been extensively investigated. Despite the central importance of protein adsorption on cell−material interactions, the quantitative analysis to probe into the role of physicochemical factors in protein adsorption remains largely unexplored in biomaterials science. In recent studies, the critical role of electric field stimulation toward the modulation of cell functionality in implantable biomaterials has been experimentally demonstrated. Given this background, we investigated the influence of external electric field stimulation (upto 1.00 V/nm) on fibronectin (FN) adsorption on a hydroxyapatite (HA) (001) surface at 300 K using the all-atom molecular dynamics (MD) simulation method. FN adsorption was found to be governed by attractive electrostatic interactions, which changed with the electric field strength. Nonmonotonous changes in the structural integrity of FN were recorded with the change in the field strength and direction. This can be attributed to the spatial rearrangement of the positions of local charges and the global structural changes of proteins. The dipole moment vectors of FN, water, and HA quantitatively exhibited a similar pattern of orienting themselves parallel to the field direction, with field strength-dependent increase in their magnitudes. No significant change has been recorded for the radial distribution function of water surrounding FN. Field-dependent variation in the salt bridge nets and the number of hydrogen bonds between FN and HA were also examined. One of the important results in the context of cell−material interaction is that the RGD (Arg-Gly-Asp) sequence of FN was exposed to the solvent side when the field was applied along an outward direction perpendicular to the HA (001) surface. In summary, the present study provides molecular insights into the influence of electric field stimulation on phenomenological interactions involved in FN adsorption on the HA surface.