Several diverse projects are being pursued. These are the major ones: Computational study of nitrogen oxides Nitric oxide (NO) is one of the simplest biological molecules in nature, but also in nearly every phase of biology and medicine with its role ranging from a critical endogenous regulator to blood flow, a principal neurotransmitter, to major pathophysiological mediator of inflammation and host defense, and so on. In the collaboration with Dr. David Wink, we applied electronic structure calculation of NO and its sequential reactions in aqueous solution. Our computational study provided theoretical foundation to understand the mechanism of NOs functions in biological systems. QM/MM Study of firefly luciferase as bioluminescence system Despite extensive studies of firefly luciferase, the color tuning mechanism of this bioluminescence protein is still unknown. In the collaboration with Dr. Yihan Shao and Ms. Shushu Zhang, we applied QM/MM methods to calculate the ground and excited states of the luciferase-luciferin complex. The adsorption and emission of luciferin at the luciferase binding site were calculated and compared to the gas phase and implicit solvent model results to reveal the key factors from protein environment in color tuning mechanism. Aplysia californica cell adhesion The Aplysia californica cell adhesion molecule (apCAM) is essential to cell-cell recognition and plays an important role in neural growth and regeneration. A detailed understanding of the apCAM-apCAM molecular adhesion mechanism is required, but the exact structure of the molecule has not yet been determined experimentally. In this study, a variety of approaches were used to test and refine atomically-detailed homology-based molecular models of the Fn domains in the extracellular part of apCAM. Long, classical all-atom molecular dynamics (MD) simulations with explicit water molecules were carried out on each Fn domain separately, and also in tan- dem. The results of the investigation suggest that the homology-based molecular models are valid. Elastic network modelling and normal mode analysis show that the beta sheets are quite rigid, but the linkers and loops have significant flexibility and are free to take part in apCAM-apCAM inter- action. Residues 624 to 631, which were initially assigned to the Fn1 domain based on biochemical considerations, have been shown by structural analysis to belong to the Fn2 domain. Stabilisation of the hinge structure of the Fn1-Fn2 tandem by salt bridges and repulsion of like charges was observed. Protein switches Many proteins involved in cellular signal transduction switch between inactive and active conformations upon binding or release of ligands. In Escherichia coli, AraC protein is involved in regulation of the expression of genes whose products enable the cells to take up and catabolize the sugar, L-arabinose. Upon binding of arabinose AraC undergoes a conformational change and actively represses its own synthesis. Mutations of residue Phe-15 render the protein unresponsive to binding of arabinose. It is not clear from experiments why this should be the case, especially if a hydrophobic residue is replaced with another hydrophobic residue. We have now completed simulations of 19 variants of this protein with substitution in position 15 with the Self-guided Langevin dynamics method in CHARMM. The simulations suggest that not only hydrophobicity but the shape of the group matter - only simulations with Trp-15 behave in a similar fasnion to the wild type. Several mutants that appeared to exhibit interesting behavior were synthesized and characterized experimentally by our collaborator Prof. Robert Schleif at Johns Hopkins University. The simulations were found to agree qualitatively with experiments. Conformational Relaxation and Water Penetration Triggered by the Ionization of Internal Groups in Proteins Ionization of internal groups in proteins is at the core of energy transduction in biological systems. The ionization can trigger conformational rearrangements, which in turn can change the pKa values of ionizable groups. To study how the protein responds to the ionization of internal groups, we have performed molecular dynamics simulations of eighteen variants of staphylococcal nuclease (SN) in which ionizable groups are buried in the protein core. The work was performed in collaboration with Prof. Bertrand Garcia-Moreno at Johns Hopkins University, who has experimentally characterized a large number of variants of SN. Our results show how the ionization of internal groups can lead to significant increases in hydration and changes in the conformation of the internal side chains and to localized backbone relaxation. These findings will be used to guide the development of more accurate methods for structure-based pKa calculations. Structure and Reaction Mechanisms of Boronic Acids Two specific areas of boronic acid (BA) research are ongoing: the design of BA based synthetic receptors and the discovery of chemical mechanisms for BA based proteasome inhibitors. This effort has elucidated the experimentally suggested reaction mechanism for the metabolism of the proteasome inhibitor, bortezomib. Proteasome inhibition and BA sensor mechanisms will continue to be studied via QM and QM/MM methods making use of the MSCAle interface within CHARMM that has been implemented this past year. These studies will also make use CHARMMs reaction path algorithms. A new collaboration with Professor Eric Anslyn of the University of Texas has led to the determination of how boronic acid sensing of sugars actually occurs via photoinduced electron transfer (PET). These results are to be extended to the future design of sensors for glycoprotein detection and identification in Collaboration with John Fossey (University of Birmingham, UK) and Tony D. James (University of Bath, UK). Cell surface saccharides function as identity tags, marking specific diseases. The ability to detect these glyco-structures is an active area of research and BA based receptors are ideal for use in distinguishing glycosylated saccharides. Effects of mechanical stress In collaboration with Dr. Edward OBrien (University of Cambridge, UK), molecular dynamics simulations with CHARMM are being performed to compute the effects of mechanical stress on the peptide bond formation within the ribosome. Our hypothesis suggests that forces on the growing peptide chain within in the ribosome may influence the chemical rate of peptide bond formation. Enzymatic activity of MMP-1 on collagen type I molecule Degradation of collagen is an important process in atherosclerosis, tissue remodeling and cancer. Matrix metalloproteinases cleave triple helical collagen structure at a specific single site in a sequences of binding and conformational changes that are not clearly understood by experiments and kinetic studies. Furthermore, native collagen usually undergoes mechanical forces in working condition that is difficult to recapitulate in experiments. In this work, we have been applying molecular dynamics simulation tools structure building, docking self-guided langevin dynamics and quantum/classical molecular mechanics to study in details the process in which matrix metalloproteinase-1 binds to and causes conformational changes of a collagen segment containing the cleavage site under tensile force. Molecular dynamics simulation and docking of MMP-1 on the cleavage site segment of collagen have produced results showing that tensile force can stabilize collagen cleavage site thus can increase resistance of collagen to cleaving by MMP-1. Self-guided langevin dynamics and quantum mechanics/molecular mechanics simulations of docked complexes are expected to yield details of enzymatic reaction of matrix metalloproteinases on collagen.

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Tofoleanu, Florentina; Lee, Juyong; Pickard Iv, Frank C et al. (2017) Absolute binding free energies for octa-acids and guests in SAMPL5 : Evaluating binding free energies for octa-acid and guest complexes in the SAMPL5 blind challenge. J Comput Aided Mol Des 31:107-118
Lee, Juyong; Tofoleanu, Florentina; Pickard 4th, Frank C et al. (2017) Absolute binding free energy calculations of CBClip host-guest systems in the SAMPL5 blind challenge. J Comput Aided Mol Des 31:71-85
Jones, Michael R; Brooks, Bernard R; Wilson, Angela K (2016) Partition coefficients for the SAMPL5 challenge using transfer free energies. J Comput Aided Mol Des 30:1129-1138
Pickard 4th, Frank C; König, Gerhard; Tofoleanu, Florentina et al. (2016) Blind prediction of distribution in the SAMPL5 challenge with QM based protomer and pK a corrections. J Comput Aided Mol Des 30:1087-1100
König, Gerhard; Mei, Ye; Pickard 4th, Frank C et al. (2016) Computation of Hydration Free Energies Using the Multiple Environment Single System Quantum Mechanical/Molecular Mechanical Method. J Chem Theory Comput 12:332-44
König, Gerhard; Pickard 4th, Frank C; Huang, Jing et al. (2016) Calculating distribution coefficients based on multi-scale free energy simulations: an evaluation of MM and QM/MM explicit solvent simulations of water-cyclohexane transfer in the SAMPL5 challenge. J Comput Aided Mol Des :
Rinschen, Markus M; Bharill, Puneet; Wu, Xiongwu et al. (2016) The ubiquitin ligase Ubr4 controls stability of podocin/MEC-2 supercomplexes. Hum Mol Genet 25:1328-44
Tan, Ming-Liang; Miller, Benjamin T; Te, Jerez et al. (2015) Hydrophobic hydration and the anomalous partial molar volumes in ethanol-water mixtures. J Chem Phys 142:064501
Tofoleanu, Florentina; Brooks, Bernard R; Buchete, Nicolae-Viorel (2015) Modulation of Alzheimer's A? protofilament-membrane interactions by lipid headgroups. ACS Chem Neurosci 6:446-55
Lee, Juyong; Joo, Keehyoung; Brooks, Bernard R et al. (2015) The Atomistic Mechanism of Conformational Transition of Adenylate Kinase Investigated by Lorentzian Structure-Based Potential. J Chem Theory Comput 11:3211-24

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