Molecular Mechanics Force Research Articles

Molecular jackhammers eradicate cancer cells by vibronic-driven action.

Through the actuation of vibronic modes in cell-membrane-associated aminocyanines, using near-infrared light, a distinct type of molecular mechanical action can be exploited to rapidly kill cells by necrosis. Vibronic-driven action (VDA) is distinct from both photodynamic therapy and photothermal therapy as its mechanical effect on the cell membrane is not abrogated by inhibitors of reactive oxygen species and it does not induce thermal killing. Subpicosecond concerted whole-molecule vibrations of VDA-induced mechanical disruption can be achieved using very low concentrations (500 nM) of aminocyanines or low doses of light (12 J cm-2, 80 mW cm-2 for 2.5 min), resulting in complete eradication of human melanoma cells in vitro. Also, 50% tumour-free efficacy in mouse models for melanoma was achieved. The molecules that destroy cell membranes through VDA have been termed molecular jackhammers because they undergo concerted whole-molecule vibrations. Given that a cell is unlikely to develop resistance to such molecular mechanical forces, molecular jackhammers present an alternative modality for inducing cancer cell death.

Methyl-Cyclohexane Methanol (MCHM) Isomer-Dependent Binding on Amorphous Carbon Surfaces.

In January 2014, over 10,000 gallons of methyl-cyclohexane methanol (MCHM) leaked into the Elk River in West Virginia, in a chemical spill incident that contaminated a large portion of the state’s water supply and left over 300,000 residents without clean water for many days and weeks. Initial efforts to remove MCHM at the treatment plant centered on the use of granulated activated carbon (GAC), which removed some of the chemical from the water, but MCHM levels were not lowered to a “non-detect” status until well after the chemical plume had moved downstream of the intake. Months later, MCHM was again detected at the outflow (but not the inflow) at the water treatment facility, necessitating the full and costly replacement of all GAC in the facility. The purpose of this study is to investigate the hypothesis that preferential absorbance of one of the two MCHM isomers, coupled with seasonal variations in water temperature, explain this contrary observation. Calculated intermolecular potentials between ovalene (a large planar polycyclic aromatic hydrocarbon) and the MCHM isomers were compared to physisorption potentials of MCHM onto an amorphous carbon model. While a molecular mechanics (MM) force field predicts no difference in the average interaction potentials between the cis- and trans-MCHM with the planar ovalene structure, MM predicts that the trans isomer binds stronger than the cis isomer to the amorphous carbon surface. Semi-empirical and density functional theory also predict stronger binding of trans-MCHM on both the planar and amorphous surfaces. The differences in the isomer binding strengths on amorphous carbon imply preferential absorbance of the trans isomer onto activated charcoal filter media. Considering seasonal water temperatures, simple Arrhenius kinetics arguments based on these predicted binding energies help explain the environmental observations of MCHM leeching from the GAC filters months after the spill. Overall, this work shows the important implications that can arise from detailed interfacial chemistry investigations.

Abstract 770: Potential Explanation of the Mechanism for Loss of Function with G233D Mutation in Platelet Glycoprotein Ibα: Results fromMolecular Dynamics Simulation

Background: Platelet play crucial role for the onset of acute coronary syndrome. The initial binding following vessel injury is exclusively mediated by the binding of von Willebrand factor (VWF) and platelet glycoprotein (GP) Ib α . Previous biological experiments revealed loss of function of platelet expressing GPIb α with G233D mutation. Objective: To elucidate the mechanism underlining the loss of function in G233D mutant. Methods: Dynamic fluctuating three-dimensional structures and the Potential of Mean Force (PMF) were calculated for the binding of VWF and platelet GPIb α in wild-type or G233D mutant. PMF were calculated at each 0.5Å for 25 Å to 65 Å of mass center distance between GPIb α and VWF. The energy required to dissociate the bond between GPIb α and VWF was calculated by subtracting the lowest PMF from the PMF at 65 Å mass center distance. Chemistry at HARvard Molecular Mechanics (CHARMM) force field with NAnoscale Molecular Dynamics (NAMD) was used for calculation. The initial structure of each mutant was obtained by inducing single amino-acid substitution with Visual Molecular Dynamics (VMD) to the stable water-soluble binding structure of wild-type VWF and GPIb α . Results: The energetically most stable binding structure of VWF and GPIb α in wild-type and G233D did not differ substantially (Figure panel A). However, The energy required to dissociate the bond between GPIb α and VWF was 4.32 kcal/mol (19.5 %) lower for G233D mutant compared to wild-type (Figure panel B). Conclusions: Our results suggest that the reduction of dissociation energy of single molecule of G233D GPIb α mutant as a possible explanation for the reduced platelet adhesion under blood flow condition.

SYNTHESIS OF VARIOUS DITHIOCARBAMATE ESTERS THROUGH REGIOSELECTIVE THIOLATION OF 2-AMINOTHIAZOLE

Dithiocarbamates are of significant importance as pesticides, vulcanizing agents and pharmaceuticals. In search of efficient regioselective strategy, the various dithiocarbamate esters were synthesized by regioselective thiolation at endo-cyclic nitrogen of 2- aminothiazole. The treatment of Boc-protected 2-aminothiazole with carbon disulphide and alkyl halide in the presence of potassium hydroxide in DMF afforded Boc-dithiocarbamate esters (3a-h). The removal of protecting group with TFA provided corresponding dithiocarbamate esters (4a-h). The formation of regioselective product was confirmed by spectral and molecular mechanical MM2 force field and PM3 approximation MOPAC energy minimization data. The strategy provides an important methodology for regioselective thiolation.

From fast light-activated processes in biomolecules to large-scale aggregation of membrane proteins: molecular dynamics simulations at different time and length scales

Molecular dynamics (MD) simulations can yield the structural dynamics of biomolecules at a femtoseconds time resolution and, simultaneously, at atomic spatial resolution. However, due to the large computational effort involved, MD was hitherto limited to rather small systems, such as a single molecule in water, and to timescales of a few hundred nanoseconds. Furthermore, the current molecular mechanical (MM) force fields cannot describe the making and breaking of chemical bonds or light-activated processes, which requires a quantum mechanical description.

Isolation, NMR spectroscopy, and conformational analysis of the antibiotic ina 2770 (cineromycin B) produced by Streptomyces strain

The antibiotic INA 2770 active against methicillin-resistant staphylococcus aureus (MRSA) was biotechnologically produced and isolated. This antibiotic is identical to cineromycin B. The characteristic features of the 1H and 13C NMR spectra of this compound were studied for the first time, and the conformational analysis was carried out by computational methods (molecular mechanics (MM3) force field) and using nuclear Overhauser effect experiments.

A CC2 dielectric continuum model and a CC2 molecular mechanics model

In this paper we present theory and applications for the second-order approximate singles and doubles coupled cluster (CC2) electronic structure method coupled to either a dielectric continuum (the CC2/DC model) or a molecular mechanical intermolecular force field (the CC2/MM model). Calculations of the interaction energy, solvation energy, electric dipole moment and electric quadrupole moment of liquid water are presented using the correlated CC2 approach. The results are compared to the corresponding results using the uncorrelated Hartree-Fock (HF) and the correlated coupled cluster singles and doubles (CCSD) methods. Also, a hierarchy in the coupling between the quantum mechanical (QM) and the molecular mechanical (MM) part of the system is investigated in the QM/MM model for the three different electronic structure methods.

Molecular mechanics (MM3) parameterization for oxocarbenium ions

The physical properties of a diverse group of 12 oxocarbenium ions have been studied with ab initio calculations at the MP2/6-31+G* level of theory. Based on theoretically derived properties such as molecular equilibrium geometry, dipole moment, and vibrational frequencies, a molecular mechanics (MM3) force field has been developed with the assistance of the programs TORSMART and MPMSR, components of our artificial parameter development and refinement method. The MM3 force field is now able to reproduce bond lengths, bond angles, moments of inertia, dipole moments, torsional energy profiles, and vibrational frequencies of oxocarbenium ions, which will allow further studies of glycoside hydrolysis and their rates of reaction. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 329–339, 2000

Electrostatic models for computing protonation and redox equilibria in proteins.

Electrostatic interactions are the most relevant for understanding biochemical systems. Acid-base and redox reactions create or destroy unit charges in biomolecules and can thus be fundamental for their function. Besides association reactions and chemical modi®cations such as phosphorylations, they are the reason for changes in protein properties. Protonation or deprotonation of titratable groups can cause changes in binding anities, enzymatic activities, and structural properties. Very often, protonations or deprotonations are the key events in enzymatic reactions. The reduction or oxidation of redox-active groups has a similar importance. In particular, the reduction of disul®de bonds can cause unfolding or functionally important conformational transitions. Consequently, the function of most proteins depends crucially on the pH and on the redox potential of the solution. Acidic denaturation of proteins in the stomach is a prerequisite for protein degradation during digestion. Beside this rather unspeci®c e€ect, the environment can tune the physiological properties of proteins in a speci®c manner. Di€erent values of pH or redox potential in di€erent organs, tissues, cells, or cell compartments steer protein function. Physiological redox and pH bu€ers such as glutathione and phosphates control these environmental parameters in living systems strictly. A few examples emphasize the physiological importance of pH and redox potential. The pH gradient in mitochondria or chloroplasts drives ATP synthesis. This pH gradient is in both systems generated by several proton transfer steps that couple to a sequence of redox reactions. In hemoglobin, pH in uences O2 binding and thus regulates O2 release during blood circulation. This behavior is also known as the Bohr e€ect. Pepsinogen cleaves itself in an acidic environment to the highly active peptidase pepsin. Membrane fusion during in uenza virus infection involves large pH-induced structural changes of the protein hemagglutinin. Because of their outstanding signi®cance, electrostatic interactions in proteins have been investigated intensively in the last decades (for review see Warshel and Russel 1984; Harvey 1989; Sharp and Honig 1990; Bashford 1991; Warshel and AE qvist 1991; Moult 1992; Madura et al. 1994; Sharp 1994; Gilson 1995; Honig and Nicholls 1995; Beroza and Case 1998; Warshel and Papazyan 1998). Several di€erent approaches are used to describe the electrostatics of proteins. The most detailed descriptions can be made by quantum-chemical approaches (Szabo and Ostlund 1989; Ziegler 1991; Lowe 1993; Naray-Szabo and Ferenczy 1995; Baerends and Gritsenko 1997). Such computationally expensive methods, however, only work for relatively small molecules and peptides. A cruder approximation must be chosen for larger systems such as solvated proteins. Molecular mechanics force ®elds are widely used for that purpose (Karplus and Petsko 1990; van Gunsteren and Berendsen 1990; Brooks and Case 1993; Kollman 1993). In these force ®elds, electrostatic interactions are modeled by (screened) Coulomb potentials. Most often, the solvent is considered explicitly in these approaches, i.e., at a microscopic level. In these simulations, fractions of unit charges ± so-called atomic partial charges ± are assigned to each atom. The atomic partial charges are adjusted to ®t the electrostatic potential obtained from a quantum-chemical calculation of small molecules with equivalent chemical groups (Breneman and Wiberg 1990). Such atomic partial charges are also used in continuum electrostatic approaches that rely on the soEur Biophys J (1999) 28: 533±551 O Springer-Verlag 1999