Sandeep Patel

Phosphorylation and dephosphorylation of proteins by kinases and phosphatases are central to cellular responses and function. The structural effects of serine and threonine phosphorylation were examined in peptides and in proteins, by circular dichroism, NMR spectroscopy, bioinformatics analysis of the PDB, small-molecule X-ray crystallography, and computational investigations. Phosphorylation of both serine and threonine residues induces substantial conformational restriction in their physiologically more important dianionic forms. Threonine exhibits a particularly strong disorder-to-order transition upon phosphorylation, with dianionic phosphothreonine preferentially adopting a cyclic conformation with restricted ϕ ( ϕ ∼ –60°) stabilized by three noncovalent interactions: a strong intraresidue phosphate-amide hydrogen bond, an n→π* interaction between consecutive carbonyls, and an n→σ* interaction between the phosphate Oγ lone pair and the antibonding orbital of C–Hβ that restricts the χ ₂ side chain conformation. Proline is unique among the canonical amino acids for its covalent cyclization on the backbone. Phosphothreonine can mimic proline’s backbone cyclization via noncovalent interactions. The preferred torsions of dianionic phosphothreonine are ϕ,ψ = polyproline helix or α-helix ( ϕ ∼ –60°); χ ₁ = g ⁻ ; χ ₂ = eclipsed C–H/O–P bonds. This structural signature is observed in diverse proteins, including the activation loops of protein kinases and protein-protein interactions. In total, these results suggest a structural basis for the differential use and evolution of threonine versus serine phosphorylation sites in proteins, with serine phosphorylation typically inducing smaller, rheostat-like changes, versus threonine phosphorylation promoting larger, step function-like switches, in proteins.

Conventional classical force fields by construction do not explicitly partition intermolecular interactions to include polarization and charge transfer effects, whereas fully quantum mechanical treatments allow a means to effect this dissection (although not uniquely due to the lack of a charge transfer operator). Considering the importance of polarization in a variety of systems, a particular class of classical models, charge equilibration models, have been extensively developed to study those systems; since these types of interaction models are inherently based on movement of charge throughout a system, they are natural platform for including polarization and charge transfer effects within the context of molecular simulations. Here, we present two bond‐space charge equilibration models we term as QE2 and mixed QE2 treat charge transfer in classical molecular mechanical calculations those provide practical solutions to two major drawbacks of charge equilibration models: (a) a nonvanishing amount of charge transfer between two heteroatoms at large separations, and (b) superlinear polarizability scaling during bond dissociation due to charge transfer over unphysical, large distances. To control charge transfer during dissociation of a bond in a molecular system, we introduce a distance‐dependent scaling function (QE2 model) which, controls and recovers physical behavior of the homonuclear and heteronuclear charge transfer between two atoms at small and large values of internuclear separation; and the mixed QE2 model in which we combine the QE2 model under allow and disallow charge transfer situations that describe both charge transfer and polarizability in a distance‐dependent manner. We demonstrate the utility of both models in the case of a water dimer, and compare the results with other existing models, and further, we perform short molecular dynamics simulations for few water clusters with the QE2 model to show the charge transfer and internuclear separation are correlated in dynamics.

Supramolecular helices with left and right handed chirality were designed and synthesized based on l-tryptophan that undergo helical inversion upon addition of H₂PO₄⁻.

Thiols can engage favorably with aromatic rings in S–H/π interactions, within abiological systems and within proteins. However, the underlying bases for S–H/π interactions are not well understood. The crystal structure of Boc-l-4-thiolphenylalanine tert-butyl ester revealed crystal organization centered on the interaction of the thiol S–H with the aromatic ring of an adjacent molecule, with a through-space H_thiol···C_aromatic distance of 2.71 Å, below the 2.90 Å sum of the van der Waals radii of H and C. The nature of this interaction was further examined by DFT calculations, IR spectroscopy, solid-state NMR spectroscopy, and analysis of the Cambridge Structural Database. The S–H/π interaction was found to be driven significantly by favorable molecular orbital interactions, between an aromatic π donor orbital and the S–H σ* acceptor orbital (a π → σ* interaction). For comparison, a structural analysis of O–H/π interactions and of cation/π interactions of alkali metal cations with aromatic rings was conducted. Na⁺ and K⁺ exhibit a significant preference for the centroid of the aromatic ring and distances near the sum of the van der Waals and ionic radii, as expected for predominantly electrostatic interactions. Li⁺ deviates substantially from Na⁺ and K⁺. The S–H/π interaction differs from classical cation/π interactions by the preferential alignment of the S–H σ* toward the ring carbons and an aromatic π orbital rather than toward the aromatic centroid. These results describe a potentially broadly applicable approach to understanding the interactions of weakly polar bonds with π systems.

Ion specific effects are ubiquitous in chemistry and biology.

Coarse-grain molecular simulations explore thermodynamics of HIV1-TAT permeation into mixed model bilayers of varying concentrations and cholesterol content. The role and nature of transmembrane pores are investigated.

In this study, we examine the temperature dependence of free energetics of nanotube association using graphical processing unit‐enabled all‐atom molecular dynamics simulations (FEN ZI) with two (10,10) single‐walled carbon nanotubes in 3 m NaI aqueous salt solution. Results suggest that the free energy, enthalpy and entropy changes for the association process are all reduced at the high temperature, in agreement with previous investigations using other hydrophobes. Via the decomposition of free energy into individual components, we found that solvent contribution (including water, anion, and cation contributions) is correlated with the spatial distribution of the corresponding species and is influenced distinctly by the temperature. We studied the spatial distribution and the structure of the solvent in different regions: intertube, intratube and the bulk solvent. By calculating the fluctuation of coarse‐grained tube‐solvent surfaces, we found that tube–water interfacial fluctuation exhibits the strongest temperature dependence. By taking ions to be a solvent‐like medium in the absence of water, tube–anion interfacial fluctuation shows similar but weaker dependence on temperature, while tube–cation interfacial fluctuation shows no dependence in general. These characteristics are discussed via the malleability of their corresponding solvation shells relative to the nanotube surface. Hydrogen bonding profiles and tetrahedrality of water arrangement are also computed to compare the structure of solvent in the solvent bulk and intertube region. The hydrophobic confinement induces a relatively lower concentration environment in the intertube region, therefore causing different intertube solvent structures which depend on the tube separation. This study is relevant in the continuing discourse on hydrophobic interactions (as they impact generally a broad class of phenomena in biology, biochemistry, and materials science and soft condensed matter research), and interpretations of hydrophobicity in terms of alternative but parallel signatures such as interfacial fluctuations, dewetting transitions, and enhanced fluctuation probabilities at interfaces.

Cell-penetrating and antimicrobial peptides show a remarkable ability to translocate across physiological membranes. Along with factors such as electric-potential-induced perturbations of membrane structure and surface tension effects, experiments invoke porelike membrane configurations during the solute transfer process into vesicles and cells. The initiation and formation of pores are associated with a nontrivial free-energy cost, thus necessitating a consideration of the factors associated with pore formation and the attendant free energies. Because of experimental and modeling challenges related to the long time scales of the translocation process, we use umbrella sampling molecular dynamics simulations with a lipid-density-based order parameter to investigate membrane-pore-formation free energy employing Martini coarse-grained models. We investigate structure and thermodynamic features of the pore in 18 lipids spanning a range of headgroups, charge states, acyl chain lengths, and saturation. We probe the dependence of pore-formation barriers on the area per lipid, lipid bilayer thickness, and membrane bending rigidities in three different lipid classes. The pore-formation free energy in pure bilayers and peptide translocating scenarios are significantly coupled with bilayer thickness. Thicker bilayers require more reversible work to create pores. The pore-formation free energy is higher in peptide–lipid systems than in peptide-free lipid systems due to penalties to maintain the solvation of charged hydrophilic solutes within the membrane environment.

The notion of direct interaction between denaturing cosolvent and protein residues has been proposed in dialogue relevant to molecular mechanisms of protein denaturation. Here we consider the correlation between free energetic stability and induced fluctuations of an aqueous–hydrophobic interface between a model hydrophobically associating protein, HFBII, and two common protein denaturants, guanidinium cation (Gdm⁺) and urea. We compute potentials of mean force along an order parameter that brings the solute molecule close to the known hydrophobic region of the protein. We assess potentials of mean force for different relative orientations between the protein and denaturant molecule. We find that in both cases of guanidinium cation and urea relative orientations of the denaturant molecule that are parallel to the local protein–water interface exhibit greater stability compared to edge-on or perpendicular orientations. This behavior has been observed for guanidinium/methylguanidinium cations at the liquid–vapor interface of water, and thus the present results further corroborate earlier findings. Further analysis of the induced fluctuations of the aqueous–hydrophobic interface upon approach of the denaturant molecule indicates that the parallel orientation, displaying a greater stability at the interface, also induces larger fluctuations of the interface compared to the perpendicular orientations. The correlation of interfacial stability and induced interface fluctuation is a recurring theme for interface-stable solutes at hydrophobic interfaces. Moreover, observed correlations between interface stability and induced fluctuations recapitulate connections to local hydration structure and patterns around solutes as evidenced by experiment (Cooper et al., J. Phys. Chem. A2014, 118, 5657.) and high-level ab initio/DFT calculations (Baer et al., Faraday Discuss2013, 160, 89).

We report free energy calculations and fluctuation profiles of single alkanes (from methane to pentane) along the direction normal to the air–water interface. The induced fluctuations and the interfacial stabilities of alkanes are found to be correlated and similar to the results of inorganic monovalent ions (Ou et al., J. Phys. Chem. B, 2013, 117, 11732). This suggests that hydrophobic solvation of solutes and ions is important in determining the adsorption behavior.