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The Chemical Computing Group Excellence Award for Graduate Students Winners for San Francisco (Fall 2014)

posted Apr 7, 2014, 8:15 AM by Emilio Xavier Esposito
The COMP Division is excited to announce the Chemical Computing Group Excellence Award for Graduate Students 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. 

Why Pucker, Sugar? Computational Chemistry Investigations into Carbohydrate Ring Distortion for Enzymatic Action
Heather B Mayes,1,2 Linda J Broadbelt,1 and Gregg T Beckham2; 1. Department of Chemical and Biological Engineering, Northwestern University and 2. National Bioenergy Center, National Renewable Energy Laboratory
Since the first crystal structure of a lysozyme was solved in the 1960s, researchers have noted that glycoside hydrolase (GH) enzymes consistently distort the conformation of the carbohydrate ring closest to the scissile bond away from the solution-stable 4C1 chair conformation. A variety of theories have been proposed to account for this feature, the most promising of which focus on favorable stereoelectronic features of puckered rings, including accumulation of positive charge at the anomeric carbon, the site of nucleophilic attack. Quantum mechanical studies are an obvious choice for investigating such hypotheses. In this work, we present the most thorough electronic structure study to date of five biologically-paramount monosaccharides in vacuum, β-xylose, α-glucose, β-glucose, β-mannose, and β-N-acetylglucosamine. Exploiting the inherently parallel problem of comparing different monosaccharide conformations, we evaluated over 123,000 geometries for the set of molecules in the study, comprising all 38 IUPAC puckering geometries and exocyclic group orientations. We employed a step-wise screening approach of increasingly accurate methods to allow rigorous examination of the differences between their properties that lend particular puckers especially amenable to catalysis. We isolated both local minima and transition states to reveal the puckering interconversion landscape of each sugar. Comparing our findings to experimental structural studies of GH substrate distortion, we found that previously proposed correlations between enzymatically employed puckers and specific catalytically favorable electronic structure properties do not persist across all sugars in the study, mirroring important differences between the sugars. Additional factors, such as interactions between exocyclic groups, must be considered in a full picture of sugar puckering. These results demonstrate that exocyclic group conformations must be explicitly considered and reveal a complex optimization problem reflecting the complexity of glycobiology. It contributes a more nuanced understanding relationship between substrate conformation and reactivity.

Effects of Spatial Organization and Molecular Scaffoldings on the Diffusive Activity of Substrates in Enzyme Nanostructures
Christopher Carver Roberts and Chia-en Chang; Department of Chemistry, University of California-Riverside
Many biological catabolic and metabolic processes occur within enzyme complexes, carried out through multi-step reaction pathways with high yield and specificity. In these complexes, the relative orientation and position of the enzymes can allow for efficient diffusion of substrates between each enzyme in the complex. Some biological complexes anchor themselves to a membrane scaffolding to retain the relative positions and orientations. These factors may play a role in creating an efficient environment for catalysis pathways, but we do not yet fully understand their contribution to the efficiency of multi-enzyme constructs. In addition, very few methods are available to systematically evaluate how spatial factors influence enzymatic activity in multi-enzyme systems. Computer modeling is a powerful tool to answer these questions. Therefore I have been developing novel coarse-grained Brownian dynamics simulation platforms, utilizing parallel computation algorithms, to rapidly evaluate different arrangements and the local environment of multi-enzyme nanostructures that affect kinetic enhancements. Using a well studied reaction-coupled enzyme pair, we attempt to approach a fundamental understanding of the effects that inter-enzyme distance, orientation, molecular scaffoldings have on the diffusive efficiency of substrates.

Rational modulation of inhibitor binding kinetics: controlling the key interactions for the slow-onset inhibition of the Mycobacterium tuberculosis enoyl-ACP reductase InhA
Cheng-Tsung Eric Lai,1,2,3 Huei-Jiun Li,2 Pan Pan,2 Weixuan Yu,2 Nina Liu,2 Peter J Tonge,1,2 and Carlos Simmerling1,2,3; 1. Graduate Program in Biochemistry and Structural Biology, Stony Brook University 2. Department of ChemistryStony Brook University, and 3. Laufer Center for Physical and Quantitative Biology, Stony Brook University 
Slow-onset inhibitors are of particular interest in drug discovery programs as the slow dissociation of the inhibitor from the target-inhibitor complex prolongs target occupancy and improves in vivo efficacy. While slow-onset inhibition is observed in many enzymes, the structural basis for slow-onset inhibition is still not generally well understood, hindering prediction and control of slow-onset binding kinetics. An enzyme system with known experimental kinetics and structure data for multiple classic and slow-onset inhibition complexes would be an ideal model system for the study of structure basis of slow-onset inhibition. InhA, the Mycobacterium tuberculosis enoyl-ACP reductase, is a validated target for the development of tuberculosis chemotherapeutics. Slow-onset inhibition of InhA follows a two-step binding mechanism in which formation of the initial enzyme-inhibitor complex is followed by a slow conformational change that leads to the final enzyme-inhibitor complex. A previous study suggests that slow-onset inhibition in InhA is correlated with ordering of the substrate-binding loop, however, the detailed mechanism is not well-understood. To bridge the gap between kinetic and structural studies of slow-onset inhibition, we used advanced molecular dynamics simulations to model the structural and energetic changes of the substrate-binding loop. The free energy profiles rationalize the binding kinetics and crystal structures observed with different inhibitors. Structural analyses identified several active-site residues that regulate the free energy barrier in the open-closed path. Mutations of these key residues led to a decreased energy at the transition state. The energy barrier can be restored by designed double mutations and inhibitors. The MD simulation predictions were validated by crystallography and kinetics experiments. These loss and regain of function studies validate these key residues controlling conformational change, and provide a platform for future design of inhibitors with better binding kinetics and in vivo potency.

Computational studies of aromatic foldamer helices: molecular encapsulation and handedness inversion
Ara M AbramyanZhiwei Liu, and Vojislava Pophristic; Department of Chemistry and Biochemistry, University of the Sciences
Foldamers are synthetic oligomers that adopt defined secondary structures in solution. The most widely observed foldamer secondary structures are helices. We use all-atom molecular dynamics simulations with improved force field parameters to study these foldamer helices. In this project we present two studies of aromatic foldamer helices: 1) molecular encapsulation; 2) helical unfolding and handedness inversion.

1) Foldamers composed of pyridine and quinoline units have experimentally been shown to form helical capsules and encapsulate small ligands. Some applications of encapsulation are molecular recognition, catalysis and drug delivery. Despite their importance, several molecular level factors determining capsule-ligand stability are missing, such as ligand binding interactions and ligand entering and leaving mechanisms. We find several important factors of consideration in the stability of capsule-ligand complexes including two possible mechanisms of ligand entering and leaving the capsule.

2) As well known, helical molecules possess handedness, which affects both their structure and function. Experimental studies have shown the stability of folded conformations and the kinetics of unfolding and handedness inversion in aromatic oligoamides derived from 8-amino-2-quinolinecarboxilic. However, the detailed atomistic picture of helix unfolding and handedness inversion is missing. By using metadynamics method, we obtain the energetics of handedness inversion and demonstrate that to change their handedness, helices do not need to fully unfold but rather a stepwise unfolding of each pitch dihedral in the helix takes place.

These studies reveal the crucial atomistic level details in the dynamics and energetics of foldamer helices and help in their rational design.

Mechanism and product specificity of PRMT1: Implications from QM and MD simulations
Symon M Gathiaka,1 Shanying Gui,2 Jun Li,3 Jun Qu,3 Joan Hevel,2 and Orlando Acevedo1; 1. Department of Chemistry and Biochemistry, Auburn University, 2. Department of Chemistry and Biochemistry, Utah State University, and 3. Department of Pharmaceutical Sciences, SUNY-Buffalo
Protein arginine methylation is emerging as a significant post-translational modification involved in various cell processes and human diseases. As the major arginine methylation enzyme, protein arginine methyltransferase 1 (PRMT1) strictly generates monomethyl arginine (MMA) and asymmetric dimethylarginine (ADMA), but not symmetric dimethylarginine (SDMA). However, it remains unclear how PRMT1 product specificity is regulated. In the current joint theoretical and experimental study, it was discovered that a single amino acid mutation (Met48 to Phe) in the PRMT1 active site enabled PRMT1 to generate both ADMA and SDMA. Quantum mechanical (QM) calculations indicated higher energy barrier of SDMA formation (CBS-QB3 ΔΔG = 3.2 kcal/mol) compared to ADMA. In addition to the unique energetic challenges for SDMA-forming methyltransferases, molecular dynamics (MD) simulations have indicated that sterics also play a major role in the selectivity. Among other highly conserved residues in the active site, residues Arg54, Glu144, Glu153's role in catalysis were evaluated. A new mechanism has been proposed that utilizes His293 to increase the nucleophilicity of the reacting arginine.