RESUMEN
The role of many-body effects in modeling silica was investigated using self-consistent force matching. Both pairwise and polarizable classical force fields were developed systematically from ab initio density functional theory force calculations, allowing for a direct comparison of the role of polarization in silica. It was observed that the pairwise potential performed remarkably well at reproducing the basic silica tetrahedral structure. However, the Si-O-Si angle that links the silica tetrahedra showed small but distinct differences with the polarizable potential, a result of the inability of the pairwise potential to properly account for variations in the polarization of the oxygens. Furthermore, the transferability of the polarizable potential was investigated and suggests that additional forces may be necessary to more completely describe silica annealing.
RESUMEN
The synthetic atomic force microscopy (AFM) method is developed to simulate a periodically replicated atomistic system subject to force and length fluctuations characteristic of an AFM experiment. This new method is used to examine the forced-extension and subsequent rupture of the alpha-helical linker connecting periodic images of a spectrin protein repeat unit. A two-dimensional potential of mean force (PMF) along the length and a reaction coordinate describing the state of the linker was calculated. This PMF reveals that the basic material properties of the spectrin repeat unit are sensitive to the state of linker, an important feature that cannot be accounted for in a one-dimensional PMF. Furthermore, nonequilibrium simulations were generated to examine the rupture event in the context of the fluctuation theorem. These atomistic simulations demonstrate that trajectories which are in apparent violation of the second law can overcome unfolding barriers at significantly reduced rupture forces.
Asunto(s)
Simulación por Computador , Microscopía de Fuerza Atómica , Complejos Multiproteicos/química , Pliegue de Proteína , Enlace de Hidrógeno , Complejos Multiproteicos/ultraestructura , Unión Proteica , Desnaturalización Proteica , Estructura Secundaria de Proteína , Termodinámica , Factores de TiempoRESUMEN
The fluctuation theorem describes the distribution of work done on small systems which have been pushed out of equilibrium in response to an external field. The theorem has recently been a subject of much interest for describing single-molecule experiments and simulations. In this communication, it is shown how the fluctuation theorem can be extended to describe fluctuations not only in the work done on a system, but also in a reaction coordinate. The extension explored in this work allows for a generalized derivation of Hummer and Szabo's expression (G. Hummer and A. Szabo, Proc. Natl. Acad. Sci. 98, 3658 (2001)) for reconstructing the potential of mean force from nonequilibrium trajectories. The derivation demonstrates how implementation of this expression can be more easily facilitated. Atomistic simulations of a biomolecular system are presented which support these results.
Asunto(s)
Algoritmos , Biología Computacional , Simulación por Computador , Transferencia de Energía , Difusión , Modelos Moleculares , Distribuciones Estadísticas , TermodinámicaRESUMEN
The unfolding pathways of multiple-repeat spectrin molecules were examined using steered molecular dynamics (SMD) simulations to forcibly unfold double- and triple-repeat spectrin molecules. Although SMD has previously been used to study other repeating-domain proteins, spectrin offers a unique challenge in that the linker connecting repeat units has a definite secondary structure, that of an alpha-helix. Therefore, the boundary conditions imposed on a double- or triple-repeat spectrin must be carefully considered if any relationship to the real system is to be deduced. This was accomplished by imposing additional forces on the system which ensure that the terminal alpha-helices behave as if there were no free noncontiguous helical ends. The results of the SMD simulations highlight the importance of the rupture of the alpha-helical linker on the subsequent unfolding events. Rupture of the linker propagates unfolding in the adjacent repeat units by destabilizing the tertiary structure, ultimately resulting in complete unfolding of the affected repeat unit. Two dominant classes of unfolding pathways are observed after the initial rupture of a linker which involve either rupture of another linker (possibly adjacent) or rupture of the basic tertiary structure of a repeat unit. The relationship between the force response observed on simulation timescales and those of experiment or physiological conditions is also discussed.
Asunto(s)
Modelos Químicos , Modelos Moleculares , Espectrina/química , Espectrina/ultraestructura , Sitios de Unión , Simulación por Computador , Reactivos de Enlaces Cruzados/química , Complejos Multiproteicos/química , Complejos Multiproteicos/ultraestructura , Unión Proteica , Desnaturalización Proteica , Pliegue de Proteína , Estructura Terciaria de Proteína , Estrés MecánicoRESUMEN
A spectrin repeat unit was subject to extension using cyclic expansion nonequilibrium molecular dynamics. Periodic boundary conditions were used to examine the effects of the contiguous alpha-helical linker on the force response. The measured force-extension curve shows a linear increase in the force response when the spectrin repeat unit is extended by approximately 0.4 nm. After that point, the force response peaks and subsequently declines. The peak in the force response marks the point where the spectrin repeat unit undergoes a change in its material properties from a strongly elastic material to a mostly viscous one, on the timescales of the simulations. The force peak is also correlated with rupture of the alpha-helical linker, and is likely the event responsible for the peaks in the sawtooth-pattern force-extension curves measured by atomic force microscopy experiments. Rupture of the linker involves simultaneously breaking approximately four hydrogen bonds that maintain the alpha-helical linker. After this initial rupture, the linker undergoes simple helix-to-coil transitions as the spectrin repeat unit continues to be extended. The implications of linker rupture in the interpretation of unfolding and atomic force microscopy experiments are also discussed.
Asunto(s)
Espectrina/química , Animales , Encéfalo/metabolismo , Pollos , Simulación por Computador , Enlace de Hidrógeno , Microscopía de Fuerza Atómica , Modelos Moleculares , Conformación Molecular , Conformación Proteica , Desnaturalización Proteica , Pliegue de Proteína , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Programas Informáticos , Factores de TiempoRESUMEN
Nonequilibrium molecular dynamics simulations were used to calculate the elastic properties of a spectrin repeat unit. A contiguous alpha-helical linker was constructed by employing periodic boundary conditions, allowing a novel scheme for evaluating the thermodynamic force as a function of extension. By measuring the force-extension response under small extensions, spectrin was observed to behave primarily as an elastic material with a spring constant of 1700 +/- 100 pN/nm. The implications of this spring constant, in terms of the properties of the spectrin tetramer, are also discussed.