Recent simulation methods for resolving molecular details in thermodynamics and kinetics

Molecular dynamics (MD) simulations are increasingly powerful tools for augmented thinking about molecular-level phenomena and their links to macroscopic properties. Fundamentally, MD propagates atomic positions and velocities by numerical integration of equations of motion subject to forces representing interatomic interactions. Unfortunately, even with present day computational power, it is nearly impossible to directly observe phenomena that have natural timescales of greater than about a microsecond or length scales greater than a few tens of nanometers using MD. This is because the ceaseless thermal agitation resolved by MD only very rarely and unpredictably rectifies itself along productive directions in some more macroscopically meaningful variable space. Our group is devoted to overcoming this issue with novel methods that provide access to these “rare events” with the ultimate aim being a full description of the equilibrium distributions and transition rates in some state space of interest. In this talk, I will highlight the development and application of some of these modern MD techniques, including temperature-acceleration and Markovian milestoning. Applications to be touched on include ligand entry and exit kinetics in enzymes and transmembrane ion transport. I will close with some highlights of future directions in method developments that involve hybrid approaches

All‐atom structural models of insulin binding to the insulin receptor in the presence of a tandem hormone‐binding element

Insulin regulates blood glucose levels in higher organisms by binding to and activating insulin receptor (IR), a constitutively homodimeric glycoprotein of the receptor tyrosine kinase (RTK) superfamily. Therapeutic efforts in treating diabetes have been significantly impeded by the absence of structural information on the activated form of the insulin/IR complex. Mutagenesis and photo‐crosslinking experiments and structural information on insulin and apo‐IR strongly suggest that the dual‐chain insulin molecule, unlike the related single‐chain insulin‐like growth factors, binds to IR in a very different conformation than what is displayed in storage forms of the hormone. In particular, hydrophobic residues buried in the core of the folded insulin molecule engage the receptor. There is also the possibility of plasticity in the receptor structure based on these data, which may in part be due to rearrangement of the so‐called CT‐peptide, a tandem hormone‐binding element of IR. These possibilities provide opportunity for large‐scale molecular modeling to contribute to our understanding of this system. Using various atomistic simulation approaches, we have constructed all‐atom structural models of hormone/receptor complexes in the presence of CT in its crystallographic position and a thermodynamically favorable displaced position. In the “displaced‐CT” complex, many more insulin–receptor contacts suggested by experiments are satisfied, and our simulations also suggest that R‐insulin potentially represents the receptor‐bound form of hormone. The results presented in this work have further implications for the design of receptor‐specific agonists/antagonists. Proteins 2013; © 2012 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98204/1/PROT_24255_sm_SuppInfo.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/98204/2/24255_ftp.pd

Intellectual Growth For Undergraduate Students: Evaluation Results From An Undergraduate Research Conference

We describe the development and evaluation of the university-wide, weeklong undergraduate research conference at the University of New Hampshire. Despite increases nationally in the number of undergraduate research conferences (URC), there has been little research examining the social and educational impact of these events on student presenters. We describe the development and evaluation of the university-wide, weeklong URC at the University of New Hampshire. A survey administered to URC participants over a four year period revealed that research culminating in a presentation at the URC was one of the more influential events students experienced during their undergraduate years and students realized a high level of satisfaction from presenting at the URC

The University of New Hampshire Engaged Scholars Academy: Instilling in Faculty Principles of Effective Partnership

Over the last decade, the University of New Hampshire (UNH) has promoted mutually beneficial partnerships between faculty and community partners vis-à-vis the Engaged Scholars Academy (ESA), a faculty development program aimed at enhancing faculty understanding of the principles of partnership and engaged scholarship. This research seeks to determine whether and how the ESA has impacted faculty-community partnerships around engaged scholarship. Findings suggest that Engaged Scholar Academy participants – as compared to non-participants – have a deeper understanding of the principles of partnership, are more likely to feel their scholarship is enhanced, spend more time with partners, engage their partners throughout the process of inquiry, and focus more on sustaining partnership outcomes

When less is more: positive population-level effects of mortality

Experimental and theoretical studies show that mortality imposed on a population can counter-intuitively increase the density of a specific life-history stage or total population density. Understanding positive population-level effects of mortality is advancing, illuminating implications for population, community, and applied ecology. Reconciling theory and data, we found that the mathematical models used to study mortality effects vary in the effects predicted and mechanisms proposed. Experiments predominantly demonstrate stage-specific density increases in response to mortality. We argue that the empirical evidence supports theory based on stage-structured population models but not on unstructured models. We conclude that stage-specific positive mortality effects are likely to be common in nature and that accounting for within-population individual variation is essential for developing ecological theory

Building a Model of Collaboration Between Historically Black and Historically White Universities

Despite increases over the last two decades in the number of degrees awarded to students from underrepresented groups in science, technology, engineering, and mathematics (STEM) disciplines, enhancing diversity in these disciplines remains a challenge. This article describes a strategic approach to this challenge—the development of a collaborative partnership between two universities: the historically Black Elizabeth City State University and the historically White University of New Hampshire. The partnership, a type of learning organization built on three mutually agreed upon principles, strives to enhance opportunities for underrepresented students to pursue careers in the STEM disciplines. This article further describes six promising practices that framed the partnership, which resulted in the submission of nine proposals to federal agencies and the funding of four grants that led to the implementation, research, learning, and evaluation that followed

What makes a young assertive bystander? The effect of intergroup contact, empathy, cultural openness, and in-Group bias on assertive bystander intervention intentions.

The present research tests the indirect effects of intergroup contact on adolescents’ bystander intervention intentions via four potential mediators: “empathy,” “cultural openness,” “in-group bias,” and “intergroup anxiety.” British adolescents (N = 855), aged 11–13 years, completed measures of intergroup (interethnic) contact and the identified indirect variables. Intended bystander behavior was measured by presenting participants with an intergroup (immigrant) name-calling scenario. Participants rated the extent to which they would behave assertively. The findings extend previous intergroup contact research by showing a significant indirect effect of intergroup contact on assertive bystander intentions via empathy, cultural openness and in-group bias (but not via intergroup anxiety). Theoretical implications and practical suggestions for future prejudice-reduction interventions are discussed

Independent but Not Indifferent: Partisan Bias in Monetary Policy at the Fed

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/96265/1/ecpo12006.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/96265/2/ecpo12006-sup-0001-AppendixS1-S13.pd

Structural Basis for Calmodulin as a Dynamic Calcium Sensor

Calmodulin is a prototypical and versatile Ca2+ sensor with EF-hands as its high-affinity Ca2+ binding domains. Calmodulin is present in all eukaryotic cells, mediating Ca2+-dependent signaling. Upon binding Ca2+, calmodulin changes its conformation to form complexes with a diverse array of target proteins. Despite a wealth of knowledge on calmodulin, little is known on how target proteins regulate calmodulin’s ability to bind Ca2+. Here, we take advantage of two splice variants of SK2 channels, which are activated by Ca2+-bound calmodulin, but show different sensitivity to Ca2+ for their activation. Protein crystal structures and other experiments show that depending on which SK2 splice variant it binds to calmodulin adopts drastically different conformations with different affinities for Ca2+ at its C-lobe. Such target protein induced conformational changes make calmodulin a dynamic Ca2+ sensor, capable of responding to different Ca2+ concentrations in cellular Ca2+ signaling