The OpenEye Outstanding Junior Faculty Award Winners for San Francisco (Fall 2014)

The COMP Division is excited to announce the OpenEye Award winners for the San Francisco ACS meeting (fall 2014). Please visit the COMP award winners and the other excellent COMP posters at the COMP Poster Session on Tuesday, August 12, 2014 from 6pm to 8pm at a location to be determined. 

How the walls come crumbling down: Elucidating mechanisms of cellulose-active enzymes using molecular simulation

Gregg T Beckham, National Renewable Energy Laboratory, National Bioenergy Center, Golden, Colorado

Carbohydrates are the most diverse set of biomolecules found in nature, and they are of central importance to many aspects of cell biology including signaling, recognition, structure, and energy storage.1 As a result of their diversity and prevalence, a huge number of enzyme classes have evolved to assemble, modify, and deconstruct carbohydrates for myriad functions of life, the study of which is important for many aspects of fundamental sciences including cell biology, biochemistry, and immunity, as well as application areas such as in human health, ecology, and renewable energy.

Plants employ carbohydrates in a dramatic, prevalent manner for their function. Namely, plant cell walls comprise a self-assembled polysaccharide matrix of cellulose, hemicellulose, and pectin interspersed with the aromatic polymer, lignin. These polymers are chemically and physically linked together to protect plant cells and to provide structure which in turn imparts structure to plant tissues. Cellulose, in particular, forms the primary structural component of plants, and is the b-1,4-linked homopolymer of glucose, which forms long chains up to thousands of units long, which in turn pack into crystalline fiber bundles. Given its prevalence in plants, cellulose is the most abundant biological material on Earth, thus serves as a massive carbon sink and a food source for a huge variety of organisms. However, cellulose is in insoluble polymer that packs into dense crystals, and glycosidic bonds in polysaccharides like cellulose are 2 and 4 orders of magnitude stronger than those in DNA or peptide bonds, respectively.2 Both of these facts imply that the enzymes that deconstruct cellulose need to exhibit multiple functions including strong binding to an insoluble substrate, either binding to the substrate internal to a polymer chain or finding and complexing to a free chain end, and then decrystallizing a chain of cellulose from the polymer, cleaving a glycosidic bond, and continuing the process along the polymeric substrate. Cellulose-degrading enzymes are typically multi-modular, exhibiting at least a catalytic domain for conducting hydrolysis reactions and a carbohydrate-binding module (CBM) for binding the whole enzyme to insoluble cellulose crystals. A flexible, O-glycosylated linker typically connects these domains. Identification of the rate-limiting step in this multi-step process is of crucial importance for identifying targets for improving these enzymes, a problem of paramount importance for biofuels production.

1. Stern, R.; Jedrzejas, M. J., Chem. Rev. 2008, 108 (12), 5061-5085.

2. Wolfenden, R.; Lu, X.; Young, G., J. Am. Chem. Soc. 1998, 120 (27), 6814-6815.

Quantum fluctuations in hydrogen bond networks: from atmospheric science to enzyme catalysis

Thomas E Markland, Department of Chemistry, Stanford University, Stanford, California

Over the past decades molecular simulation has become an increasingly important tool in predicting and interpreting chemical processes. Inherent in these simulations is the assumption that the nuclei behave classically. However, for processes involving light particles such as hydrogen the quantum mechanical nature of the particles can dramatically alter their structure and dynamics. I will present our recent advances in developing approaches to treat nuclear quantum mechanical fluctuations in condensed phase systems and to calculate isotope effects at a cost barely more than the a corresponding classical simulation. These advances allow us to investigate, in unprecedented detail, chemical systems where the inclusion of quantum mechanical effects is essential to obtain the correct result. I will illustrate the utility of these approaches with recent applications ranging from fractionation of hydrogen isotopes between liquid water and its vapor, which are a major input in climate modeling, to the biologically important proton delocalization in enzyme active sites. 

Affordable multiscale free energy simulations: A novel method that efficiently connects low level sampling to QM/MM via Non-Boltzmann Bennett reweighting

Henry Lee Woodcock, University of South Florida, Department of Chemistry, Tampa, Florida

Herein, we describe how a novel Non-Boltzmann Bennett reweighting scheme can be combined with the indirect QM/MM FES approach to avoid expensive QM simulations. Details of this new approach (i.e., QM-NBB) are presented with particular emphasis on connecting MM and QM levels of theory. QM-NBB is then applied to a number of test cases in explicit and implicit solvent with both absolute and relative solvation free energy differences computed. Further, QM-NBB is compared critically to the standard FEP based indirect scheme and some best practices are suggested for improving methods that seek to connect MM to QM (or QM/MM) levels of theory in FES.

Targeting membrane interfaces for computer-aided drug design and drug delivery applications

Zoe Cournia, Biomedical Research Foundation of the Academy of Athens, Pharmacology, Athens, Greece