Misfolding and aggregation of prion proteins are associated with several neurodegenerative diseases. Therefore, understanding the mechanism of the misfolding process is of enormous interest in the scientific community. It has been speculated and widely discussed that the native cellular prion protein (PrP) form needs to undergo substantial unfolding to a more stable PrP state, which may further oligomerize into the toxic scrapie (PrP) form. Here, we have studied the mechanism of the unfolding of the human prion protein (huPrP) using a set of extensive well-tempered metadynamics simulations. Through multiple microsecond-long metadynamics simulations, we find several possible unfolding pathways. We show that each pathway leads to an unfolded state of lower free energy than the native state. Thus, our study may point to the signature of a PrP form that corresponds to a global minimum on the conformational free-energy landscape. Moreover, we find that these global minima states do not involve an increased β-sheet content, as was assumed to be a signature of PrP formation in previous simulation studies. We have further analyzed the origin of metastability of the PrP form through free-energy surfaces of the chopped helical segments to show that the helices, particularly H2 and H3 of the prion protein, have the tendency to form either a random coil or a β-structure. Therefore, the secondary structural elements of the prion protein are only weakly stabilized by tertiary contacts and solvation forces so that relatively weak perturbations induced by temperature, pressure, pH, and so forth can lead to substantial unfolding with characteristics of intrinsically disordered proteins.

Here, we investigate the effect of urea in the unfolding dynamics of flavin adenine dinucleotide (FAD), an important enzymatic cofactor, through steady state, time-resolved fluorescence spectroscopic and molecular dynamics (MD) simulation studies. Steady state results indicate the possibility of urea induced unfolding of FAD, inferred from increasing emission intensity of FAD with urea. The TCSPC and up-conversion results suggest that the stack-unstack dynamics of FAD severely gets affected in the presence of urea and leads to an increase in the unstack conformation population from 15% in pure water to 40% in 12 M urea. Molecular dynamics simulation was employed to understand the nature of the interaction between FAD and urea at the molecular level. Results depict that urea molecules replace many of the water molecules around adenine and isoalloxazine rings of FAD. However, the major driving force for the stability of this unstack conformations arises from the favorable stacking interaction of a significant fraction of the urea molecules with adenine and isoalloxazine rings of FAD, which overcomes the intramolecular stacking interaction between themselves observed in pure water.

Computational drug design is increasingly becoming important with new and unforeseen diseases like COVID‐19. In this study, we present a new computational de novo drug design and repurposing method and applied it to find plausible drug candidates for the receptor binding domain (RBD) of SARS‐CoV‐2 (COVID‐19). Our study comprises three steps: atom‐by‐atom generation of new molecules around a receptor, structural similarity mapping to existing approved and investigational drugs, and validation of their binding strengths to the viral spike proteins based on rigorous all‐atom, explicit‐water well‐tempered metadynamics free energy calculations. By choosing the receptor binding domain of the viral spike protein, we showed that some of our new molecules and some of the repurposable drugs have stronger binding to RBD than hACE2. To validate our approach, we also calculated the free energy of hACE2 and RBD, and found it to be in an excellent agreement with experiments. These pool of drugs will allow strategic repurposing against COVID‐19 for a particular prevailing conditions.

Ion-specific effects on peptides and proteins are key to biomolecular structure and stability. The subtle roles of the cations are far less understood, compared to the pronounced effects of the anions on proteins. Most importantly, divalent cations such as Ca2+ and Mg2+ are crucial to several biological functions. Herein, we demonstrate that an amide–iminolate equilibrium is triggered by the binding of the divalent cations to the amide oxygen in aqueous solution. The excellent agreement between the experimental and theoretical results confirms the arrest of an unusual amide tautomer by the divalent cations, which is a rarely known phenomenon that might open up an array of applications in chemistry and biology.

DNA–protein interactions regulate several biophysical functions, yet the mechanism of only a few is investigated in molecular detail. An important example is the intercalation of transcription factor proteins into DNA that produce bent and kinked DNA. Here, we have studied the molecular mechanism of the intercalation of a transcription factor SOX4 into DNA with a goal to understand the sequence of molecular events that precede the bending and kinking of the DNA. Our long well-tempered metadynamics and molecular dynamics (MD) simulations show that the protein primarily binds to the backbone of DNA and rotates around it to form an intercalative native state. We show that although there are multiple pathways for intercalation, the deintercalation pathway matches with the most probable intercalation pathway. In both cases, bending and kinking happen simultaneously, driven by the onset of the intercalation of the amino acid.

Binding of transcription factor (TF) proteins with DNA may cause severe kinks in the latter. Here, we investigate the molecular origin of the DNA kinks observed in the TF-DNA complexes using small molecule intercalation pathway, crystallographic analysis, and free energy calculations involving four different transcription factor (TF) protein-DNA complexes. We find that although protein binding may bend the DNA, bending alone is not sufficient to kink the DNA. We show that partial, not complete, intercalation is required to form the kink at a particular place in the DNA. It turns out that while amino acid alone can induce the desired kink through partial intercalation, protein provides thermodynamic stabilization of the kinked state in TF-DNA complexes.

The ability of phenol to transfer a proton to surrounding ammonia molecules in a phenol–(ammonia) n cluster depends on the relative orientation of ammonia molecules, and a critical field of about 285 MV cm–1 is essential along the O–H bond for the proton-transfer process. Ab initio MD simulations reveal that the proton-transfer process from phenol to ammonia cluster is spontaneous when the cluster has at least eight ammonia molecules, and the proton-transfer event is almost instantaneous (about 20–120 fs). These simulations also reveal that the rate-determining step for the proton-transfer process is the reorganization of the solvent around the OH group. During the solvent reorganization process, the fluctuations in the solvent occur until a particular set of configurations projects the field in excess of the critical electric field along the O–H bond which drives the proton-transfer process. Further, the proton-transfer process follows a curvilinear path which includes the O–H bond elongation and out-of-plane movement of the proton and can be referred to as a “bend-to-break” process.

Understanding quantum transport through DNAbased heterostructures is a key to advancing the field of DNA nanoelectronics, where quantum interference would play a significant role. Electronic "barriers" and "wells" can be constructed in DNA using adenine−thymine (AT) and guanine−cytosine (GC) base pairs, respectively, as their ionization potentials differ significantly. We investigate the influence of the width of barriers and wells on hole transport. Density functional theory calculations are performed on energy-minimized DNA structures, followed by quantum transport calculations including decoherence. The device physics is probed by constructing a model Hamiltonian and selectively turning off long-range and interstrand interactions. Major outcomes of the study include the following: (1) DNA heterostructures complement the solid-state semiconductor counterparts; that is, conductance decreases sharply and marginally with an increase in barrier and well width, respectively; (2) quantum interference in DNA heterostructures is robust, as seen by clear peaks in the transmission resonance even with decoherence; (3) DNA conformation has a profound role in deciding the conductance of equivalent heterostructures; and (4) structural differences lead to closer HOMO energy levels and more delocalized states. As a result, transport can be efficient in some strands even with weaker π−π orbital overlap.