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Electron transfer reaction rate constants at semiconductor/liquid interfaces are calculated using the Fermi Golden Rule and a tight-binding model for the semiconductors. The slab method and a z-transform method are employed in obtaining the electronic structures of semiconductors with surfaces and are compared. The maximum electron transfer rate constants at Si/viologen2+/+ and InP/Me2Fc+/0 interfaces are computed using the tight-binding type calculations for the solid and the extended-Huckel for the coupling to the redox agent at the interface. These results for the bulk states are compared with the experimentally measured values of Lewis and co-workers, and are in reasonable agreement, without adjusting parameters. In the case of InP/liquid interface, the unusual current vs applied potential behavior is additionally interpreted, in part, by the presence of surface states.

The transportation of membrane proteins through the aqueous subcellular space is an important and challenging process. Its molecular mechanism and the associated structural change are poorly understood. Periplasmic chaperones, such as Skp in Escherichia coli, play key roles in the transportation and protection of outer membrane proteins (OMPs) in Gram-negative bacteria. The molecular mechanism through which Skp interacts with and protects OMPs remains mysterious. Here, a combined experimental and molecular dynamics simulation study was performed to gain the structural and dynamical information in the process of OMPs and Skp binding. Stopped-flow experiments on site specific mutated and labeled Skp and several OMPs, namely OmpC, the transmembrane domain of OmpA, and OmpF, allowed us to obtain the mechanism of OMP entering the Skp cavity, and molecular dynamics simulations yielded detailed molecular interactions responsible for this process. Both experiment and simulation show that the entrance of OMP into Skp is a highly directional process, which is initiated by the interaction between the N-terminus of OMP and the bottom "tentacle" domain of Skp. The opening of the more flexible tentacle of Skp, the non-specific electrostatic interactions between OMP and Skp, and the constant formation and breaking of salt bridges between Skp and its substrate together allow OMP to enter Skp and gradually "climb" into the Skp cavity in the absence of an external energy supply.

It is well known that alcohols can have strong effects on protein structures. For example, monohydric methanol and ethanol normally denature, whereas polyhydric glycol and glycerol protect, protein structures. In a recent combined theoretical and NMR experimental study, we showed that molecular dynamics simulations can be effectively used to understand the molecular mechanism of methanol denaturing protein. In this study, we used molecular dynamics simulations to investigate how alcohols with varied hydrophobicity and different numbers of hydrophilic groups (hydroxyl groups) exert effects on the structure of the model polypeptide, BBA5. First, we showed that methanol and trifluoroethanol (TFE) but not glycol or glycerol disrupt hydrophobic interactions. The latter two alcohols instead protect the assembly of the α- and β-domains of the polypeptide. Second, all four alcohols were shown to generally increase the stability of secondary structures, as revealed by the increased number of backbone hydrogen bonds formed in alcohol/water solutions compared to that in pure water, although individual hydrogen bonds can be weakened by certain alcohols, such as TFE. The two monohydric alcohols, methanol and TFE, display apparently different sequence-dependence in affecting the backbone hydrogen bond stability: methanol tends to enhance the stability of backbone hydrogen bonds of which the carbonyl groups are from polar residues, whereas TFE tends to stabilize those involving non-polar residues. These results demonstrated that subtle differences in the solution environment could have distinct consequences on protein structures.

Our previous study showed that for the tested polypeptides which have similar β-hairpin structures but different sequences, their folding free energy pathways are dominantly determined by the turn conformational propensity. In this study, we study how the turn conformational propensity affects the structure of hairpins. The folding of two mutants of GB1p peptide (GB1m2 and GB1m3), which have the optimized turn sequence ((6)DDATK(11)T → (6)NPATG(11)K) with native structures unsolved, were simulated using integrated tempering sampling molecular dynamics simulations and the predicted stable structures were compared to wild-type GB1p. It was observed that the turn optimization of GB1p generates a more favored 5-residue type I(') turn in addition to the 6-residue type I turn in wild-type GB1p. As a result two distinctly different hairpin structures are formed corresponding to the "misfolded" (M) and the "folded" (F) states. M state is a one-residue-shifted asymmetric β-hairpin structure whereas F state has the similar symmetric hairpin structure as wild-type GB1p. The formation of the favored type I(') turn has a small free energy barrier and leads to the shifted β-hairpin structure, following the modified "zipping" model. The presence of disfavored type I turn structure makes the folding of a β-hairpin consistent with the "hydrophobic-core-centric" model. On the other hand, the folding simulations on other two GB1p mutants (GB1r1 and GBr2), which have the position of the hydrophobic core cluster further away from the turn compared to wild-type GB1p, showed that moving the hydrophobic core cluster away from the turn region destabilizes but does not change the hairpin structure. Therefore, the present study showed that the turn conformational propensity is a key factor in affecting not only the folding pathways but also the stable structure of β-hairpins, and the turn conformational change induced by the turn optimization leads to significant changes of β-hairpin structure.

Molecular dynamics simulations using the integrated tempering sampling method were performed for the folding of wild-type B domain of protein A (BdpA). Starting from random and stretched structures, these simulations allow us to fold this protein into the native-like structure frequently, achieving very small backbone (1.7 A) and all heavy-atom root-mean-square deviation (2.6 A). Therefore, the method used here increases the efficiency of configuration sampling and thermodynamics characterization by molecular dynamics simulation. Although inconsistency exists between the calculation and experiments for the absolute stabilities, as a limitation of the force field parameters, the calculated order of helix stability (H3 > H2 > H1) is consistent with that determined by experiments for individual separate helices. The lowest free energy folding pathway of BdpA was found to start with a barrierless and non-cooperative structural collapse from the entirely extended (E) state, which leads to a physiologically unfolded (P) state consisting of multiple stable structures with few native inter-helical hydrophobic interactions formed. In the P state, only H3 is fully structured. The final formation of H1 (and to a lesser extent, H2) in the folded (F) state requires the packing of the inter-helical hydrophobic contacts. In addition, it was found that stabilities of backbone hydrogen bonds are significantly affected by their positions relative to the inter-helical hydrophobic core. As temperature increases, the stability of the hydrogen bonds exposed to the solvent tends to increase while that of the hydrogen bonds buried within the hydrophobic core decreases. Finally, we discuss implications of this study on the general folding mechanism of proteins.

In this paper, based on the integrated tempering sampling we introduce a selective integrated tempering sampling (SITS) method for the efficient conformation sampling and thermodynamics calculations for a subsystem in a large one, such as biomolecules solvated in aqueous solutions. By introducing a potential surface scaled with temperature, the sampling over the configuration space of interest (e.g., the solvated biomolecule) is selectively enhanced but the rest of the system (e.g., the solvent) stays largely unperturbed. The applications of this method to biomolecular systems allow highly efficient sampling over both energy and configuration spaces of interest. Comparing to the popular and powerful replica exchange molecular dynamics (REMD), the method presented in this paper is significantly more efficient in yielding relevant thermodynamics quantities (such as the potential of mean force for biomolecular conformational changes in aqueous solutions). It is more important that SITS but not REMD yielded results that are consistent with the traditional umbrella sampling free energy calculations when explicit solvent model is used since SITS avoids the sampling of the irrelevant phase space (such as the boiling water at high temperatures).

To quantify the effects of implicit solvent model on the folding of protein, thermodynamics calculation was performed for the folding of C-terminal hairpin from B1 domain of protein G using AMBER ff96 force field and different implicit solvent models (GB(OBC) and GBn). In the multiple AMBER force fields, ff96 strongly favors the hairpin conformations whereas the other force fields (e.g., ff94 and ff99) favor the helical conformations. In recent studies ff96 was found to be better balanced for various secondary structures than other force fields. The two implicit solvent models mentioned above were shown to be the most appropriate for beta-hairpin folding [M. S. Shell et al., J. Phys. Chem. B 112, 6878 (2008)]. The free energy landscape as a function of several different reaction coordinates was studied for both solvent models. The comparison of the results from these implicit models shows that the combination of AMBER ff96 with the GB(OBC) model yields stable structures that are in better agreement with experiments and results calculated using the explicit solvent model.

We show here that constant velocity steered molecular dynamics (SMD) simulations of alpha-helices in a vacuum present a well defined plateau in the force-extension relationship for homopolypeptides having more than (approximately) twenty residues. With the processes being far away from equilibrium, the energies strongly depend on the stretching velocity. Importantly, for a given velocity variation, the energy variation depends also on the helix sequence. Additionally, our observations show that homopolypeptides made of ten different amino acids (Ala, Cys, Gln, Ile, Leu, Met, Phe, Ser, Thr and Val) present a linear helix-coil transition.

We studied the effects of hydrophobicity and dipole-dipole interactions between the nearest-neighbor amide planes on the secondary structures of a model polypeptide by calculating the free energy differences between different peptide structures. The free energy calculations were performed with low computational costs using the accelerated Monte Carlo simulation (umbrella sampling) method, with a bias-potential method used earlier in our accelerated molecular dynamics simulations. It was found that the hydrophobic interaction enhances the stability of alpha helices at both low and high temperatures but stabilizes beta structures only at high temperatures at which alpha helices are not stable. The nearest-neighbor dipole-dipole interaction stabilizes beta structures under all conditions, especially in the low temperature region where alpha helices are the stable structures. Our results indicate clearly that the dipole-dipole interaction between the nearest neighboring amide planes plays an important role in determining the peptide structures. Current research provides a more unified and quantitative picture for understanding the effects of different forms of interactions on polypeptide structures. In addition, the present model can be extended to describe DNA/RNA, polymer, copolymer, and other chain systems.

Recent experiment showed that cytoplasmic dynein 1, a molecular motor responsible for cargo transport in cells, functions as a gear in response to external load. In the presence of vanishing or small external load, dynein walks with 24- or 32-nm steps, whereas at high external load, its step size is reduced to 8nm. A simple model is proposed to account for this property of dynein. The model assumes that the chemical energy of ATP hydrolysis is used through a loose coupling between the chemical reaction and the translocation of dynein along microtubule. This loose chemomechanical coupling is represented by the loosely coupled motions of dynein along two different reaction coordinates. The first reaction coordinate is tightly coupled to the chemical reaction and describes the protein conformational changes that control the chemical processes, including ATP binding and hydrolysis, and ADP-Pi release. The second coordinate describes the translocation of dynein along microtubule, which is directly subject to the influence of the external load. The model is used to explain the experimental data on the external force dependence of the dynein step size as well as the ATP concentration dependence of the stall force. A number of predictions, such as the external force dependence of speed of translocation, ATP hydrolysis rate, and dynein step sizes, are made based on this theoretical model. This model provides a simple understanding on how a variable chemomechanical coupling ratio can be achieved and used to optimize the biological function of dynein.

Many essential functions of living cells are performed by nanoscale protein motors. The best characterized of these is F o F 1 -ATP synthase, the smallest rotary motor. This rotary motor catalyzes the synthesis of ATP with high efficiency under conditions where the reactants (ADP, H 2 PO 4 − ) and the product (ATP) are present in the cell at similar concentrations. We present a detailed structure-based kinetic model for the mechanism of action of F 1 -ATPase and demonstrate the role of different protein conformations for substrate binding during ATP synthesis and ATP hydrolysis. The model shows that the pathway for ATP hydrolysis is not simply the pathway for ATP synthesis in reverse. The findings of the model also explain why the cellular concentration of ATP does not inhibit ATP synthesis.

Gramicidin A which is composed of alternating L- and D-amino acids is a naturally occurring pentadecapeptide from Bacillus brevis known to form monovalent metal ion channels in lipid membranes. The active form is a noncovalently bound dimer. The conformation and self-assembly behavior of gramicidin A highly depends on the solution environment. In this presentation, we report the use of electrospray-ion mobility-mass spectrometry to study the conformation of alkali metals adducts of gramicidin A monomer, as well as the monomerization and conformer interconversion equilibrium of gramicidin A dimer as a function of the solvent. The conformation of gramicidin A monomer vary significantly upon binding different metal adducts. Enhanced sampling molecular dynamics simulations are performed on alkali metals adducts to provide thermodynamics information of different conformers and gain insights of the interaction of different metal ions with the monomer. The kinetics of the monomerization and conformer interconversion processes of dimer in various alcohol solutions (Ethanol, 1-Propanol and, Isobutanol) are monitored by using the ion mobility profile of the monomer and the dimer. The rate constants and the temperature dependence of the rate constants of the monomer compare well with literature values which were obtained by using fluorescence. Furthermore, we found that the water content in the alcohol solution greatly influences the self-assembly process significantly. The role of water in catalyzing the conformer interconversion is being investigated further. Ion mobility spectrometry (IMS) combined with molecular dynamics simulations is a merging technique for conformational analysis of gas-phase low-lying energy level structures of biomolecules. In this study, we will demonstrate that this gas phase technique can also be of utility in studying a solution phase structural dynamics problem.