Free energy calculations of the interactions of c-Jun-based synthetic peptides with the c-Fos protein

The c-Fos–c-Jun complex forms the activator protein 1 transcription factor, a therapeutic target in the treatment of cancer. Various synthetic peptides have been designed to try to selectively disrupt the interaction between c-Fos and c-Jun at its leucine zipper domain. To evaluate the binding affinity between these synthetic peptides and c-Fos, polarizable and nonpolarizable molecular dynamics (MD) simulations were conducted, and the resulting conformations were analyzed using the molecular mechanics generalized Born surface area (MM/GBSA) method to compute free energies of binding. In contrast to empirical and semiempirical approaches, the estimation of free energies of binding using a combination of MD simulations and the MM/GBSA approach takes into account dynamical properties such as conformational changes, as well as solvation effects and hydrophobic and hydrophilic interactions. The predicted binding affinities of the series of c-Jun-based peptides targeting the c-Fos peptide show good correlation with experimental melting temperatures. This provides the basis for the rational design of peptides based on internal, van der Waals, and electrostatic interactions.

Calculations of the free energy of interaction of the c-Fos−c-Jun coiled coil: Effects of the solvation model and the inclusion of polarization effects

The leucine zipper region of activator protein-1 (AP-1) comprises the c-Jun and c-Fos proteins and constitutes a well-known coiled coil protein−protein interaction motif. We have used molecular dynamics (MD) simulations in conjunction with the molecular mechanics/Poisson−Boltzmann generalized-Born surface area [MM/PB(GB)SA] methods to predict the free energy of interaction of these proteins. In particular, the influence of the choice of solvation model, protein force field, and water potential on the stability and dynamic properties of the c-Fos−c-Jun complex were investigated. Use of the AMBER polarizable force field ff02 in combination with the polarizable POL3 water potential was found to result in increased stability of the c-Fos−c-Jun complex. MM/PB(GB)SA calculations revealed that MD simulations using the POL3 water potential give the lowest predicted free energies of interaction compared to other nonpolarizable water potentials. In addition, the calculated absolute free energy of binding was predicted to be closest to the experimental value using the MM/GBSA method with independent MD simulation trajectories using the POL3 water potential and the polarizable ff02 force field, while all other binding affinities were overestimated.

The tectonic significance of lower Permain successions in the Texas Orocline (Eastern Australia)

The Texas Orocline is a prominent orogenic curvature that developed during the early Permian in the southern New England Orogen. Outliers preserving lower Permian sedimentary successions (Bondonga, Silver Spur, Pikedale, Terrica, Alum Rock and Ashford beds) approximately outline the oroclinal structure, but the tectonic processes responsible for the development of these basinal successions, and their relationships to the Texas Orocline, are unclear. Here we address this shortcoming by providing new U–Pb detrital and primary zircon ages from these successions, as well as detailed stratigraphic and structural data from the largest exposed succession (Bondonga beds). Field observations and U–Pb geochronological data suggest that the lower Permian successions in the Texas Orocline are remnants of a single, formerly larger basin that was deposited after ca 302 Ma. Time constraints for formation of this basin are correlative with constraints from the lower Permian Nambucca Block, which was likely deposited in response to regional back-arc extension during and/or after the development of the Texas Orocline. The conclusion that the lower Permian sedimentary basins in the Texas Orocline belong to this back-arc extensional system supports the suggestion that oroclinal bending in the New England Orogen was primarily controlled by trench retreat and associated overriding-plate extension.

ACE Research Vignette 049: How Do Business Founders Use Business Plans?

This series of research vignettes is aimed at sharing current and interesting research findings from our team of international Entrepreneurship researchers. In this vignette Per Davidsson and Christophe Garonne examine the use of business planning among business start-ups.

ACE Research Vignette 050: What makes new migrant businesses grow? Connections or location?

This series of research vignettes is aimed at sharing current and interesting research findings from our team of international Entrepreneurship researchers. In this vignette, Dr. Roxanne Zolin and Dr. Artemis Chang consider both the role of ethnic connections and location in an ethnic neighbourhood on new migrant business growth.

Leading Digital Transformation: Building Technology and Information Governance Capability in Boards of Directors and the C-Suite

Information and technology and its use in organisation transformation presents unprecedented opportunities and risks. Increasingly, the Governance of Enterprise Information and Technology (GEIT) competency in the board room and executive is needed. Whether your organization is small or large, public, private or not for profit or whether your industry is not considered high-tech, IT is impacting your sector – no exceptions. But there is a skill shortage in boards: GEIT capability is concerningly low. This capability is urgently needed across the board, including those directors who come from finance, legal, marketing, operations and HR backgrounds. Digital disruption also affects all occupations. Putting in place a vision will help ensure emergency responses will meet technology-related duty of care responsibilities. When GEIT-related forward thinking and planning is carried out at the same time that you put your business strategy and plan in place, your organization has a significantly increased chance of not only surviving, but thriving into the future. Those organizations that don’t build GEIT capability risk joining the growing list of once-leading firms left behind in the digital ‘cloud of smoke’. Those organizations that do will be better placed to reap the benefits and hedge against the risks of a digital world. This chapter provides actionable, research-based considerations and processes for boards to use, to build awareness, knowledge and skills in governing technology-related organization strategy, risk and value creation.

ACE Research Vignette 051: How and Why is Small Business Managers’ Age Related To Business Growth?

This series of research vignettes is aimed at sharing current and interesting research findings from our team of international entrepreneurship researchers. This vignette, written by Professor Hannes Zacher, Professor Michael M. Gielnik and Dr Antje Schmitt, reports findings on relationships between small business managers’ age, their focus on opportunities, and business growth (sales and number of employees) over five years.

ACE Research Vignette #52: Business growth and new initiatives in small and medium manufacturing enterprises from a design innovation program

This series of research vignettes is aimed at sharing current and interesting research findings from our team of international Entrepreneurship researchers. This vignette, written by Dr Judy Matthews examines the effects of firm engagement with design innovation programs on entrepreneurial activities of small and medium enterprises.