Bulletin of the American Physical Society
APS March Meeting 2017
Volume 62, Number 4
Monday–Friday, March 13–17, 2017; New Orleans, Louisiana
Session R4: Physics of Proteins Association and Recognition IIFocus
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Sponsoring Units: DBIO DPOLY Chair: Margaret Cheung, University of Houston Room: 263 |
Thursday, March 16, 2017 8:00AM - 8:12AM |
R4.00001: Conflicting thermal response of a monomer and a tandem dimer of a membrane protein segment (hHv1) Panisak Boonamnaj, Sunita Subedi Paudel, Warin Jetsadawisut, Sunan Kitjaruwankul, Pornthep Sompornpisut, Ras Pandey Using all-atom Molecular Dynamics and a coarse-grained Monte Carlo computer simulations, we study the thermal response of the structure of monomer and dimer of C-terminal domain of the protein hHv1 which is critical for dimer assembly and regulation of proton permeation through the membrane. A knowledge-based residue-residue (KBRR) interaction matrix is used as input for the Metropolis algorithm in coarse-grained (CG) model. We are able to examine a number of local and global physical quantities as a function of temperature (T) effectively due to efficiency of the CG model. We find that the radius of gyration (Rg) of the protein increases on increasing the temperature, as one would expect, over a well-defined range. All-atom simulation data, in contradiction, shows the opposite, i.e. Rg decreases with raising the temperature. The reverse-thermal response also appears in CGMC but only in low T range. Attempts are made to understand the dichotomy by performing large-scale simulations over the entire temperature regime. [Preview Abstract] |
Thursday, March 16, 2017 8:12AM - 8:24AM |
R4.00002: Membrane permeation of self-adapting metaphilic peptides Ming Han, Michelle Lee, Gerard Wong, Erik Luijten Amphiphilic surface patterns, with both hydrophobicity and cationic charge, are crucial characteristics of antimicrobial peptides (AMPs), assisting in permeating and remodeling bacterial membranes. Like proteins, traditional AMPs often have solid-like surfaces due to strong hydrogen bonding or hydrophobicity. Here we demonstrate that adaptability of liquid-like surfaces can significantly enhance membrane-permeating activity of AMPs. These metaphilic peptides have a bottlebrush architecture consisting of a rigid core decorated with mobile, hydrophobic side chains that are terminated with cationic groups. Using molecular dynamics simulations, we find that the flexible side chains can undergo significant rearrangement when interacting with a lipid membrane, endowing the peptide with adaptable surface chemistry. [Preview Abstract] |
Thursday, March 16, 2017 8:24AM - 8:36AM |
R4.00003: Temperature- and solvent-responsive structures of CorA protein and its membrane segments Sunan Kitjaruwankul, Panisak Boonamnaj, Sunita Paudel, Warin Jetsadawisut, Pornthep Sompornpisut, Ras Pandey Solvent-responsive structures of CorA Mg$^{2+}$ channel (corA) with well-defined inner (icorA) and outer (ocorA) membrane components play a critical role in selective transport of magnesium across biological membranes. Using a coarse-grained Monte Carlo simulation, we study the effects of solvent quality on the structures of corA, icorA and ocorA at different temperatures. A knowledge-based residue-residue interaction along with a set of residue-solvent interaction (\textit{Vs}) based on the hydropathy index are used in a matrix with explicit solvent particles. We monitor targeted binding of solvent particles for a range of its interaction strength ($f)$ to emulate the underlying matrix environment. We find that the spread of the structure of corA (and ocorA) measured by the radius of gyration (Rg) responds non-monotonically (i.e. the increase of Rg followed by decay) with the interaction $f$ at higher temperature; decay of Rg with $f$ at lower T is slower. The structure of icorA remains least affected by the solvent interaction strength. Effects of emulated membrane matrix may also be presented as the data becomes available. [Preview Abstract] |
Thursday, March 16, 2017 8:36AM - 9:12AM |
R4.00004: Opposing intermolecular tuning of Ca$^{2+}$ affinity for Calmodulin by its target peptides Invited Speaker: Margaret Cheung We investigated the impact of bound calmodulin (CaM)-target compound structure on the affinity of calcium (Ca$^{2+})$ by integrating coarse-grained models and all-atomistic simulations with non-equilibrium physics. We focused on binding between CaM and two specific targets, Ca$^{2+}$/CaM-dependent protein kinase II (CaMKII) and neurogranin (Ng), as they both regulate CaM-dependent Ca$^{2+}$ signaling pathways in neurons. It was shown experimentally that Ca$^{2+}$/CaM binds to the CaMKII peptide with higher affinity than the Ng peptide. The binding of CaMKII peptide to CaM in return increases the Ca$^{2+}$ affinity for CaM. However, this reciprocal relation was not observed in the Ng peptide, which binds to Ca$^{2+}$-free CaM or Ca$^{2+}$/CaM with similar binding affinity. Unlike CaM-CaMKII peptide that allowed structure determination by crystallography, the structural description of CaM-Ng peptide is unknown due to low binding affinity, therefore, we computationally generated an ensemble of CaM-Ng peptide structures by matching the changes in the chemical shifts of CaM upon Ng peptide binding from nuclear magnetic resonance experiments. We computed the changes in Ca$^{2+}$ affinity for CaM with and without binding targets in atomistic models using Jarzynski's equality. We discovered the molecular underpinnings of lowered affinity of Ca$^{2+}$ for CaM in the presence of Ng by showing that the N-terminal acidic region of Ng peptide pries open the $\beta $-sheet structure between the Ca$^{2+}$ binding loops particularly at C-domain of CaM, enabling Ca$^{2+\, }$release. In contrast, CaMKII increases Ca$^{2+}$ affinity for the C-domain of CaM by stabilizing the two Ca$^{2+}$ binding loops. \newpage [Preview Abstract] |
Thursday, March 16, 2017 9:12AM - 9:24AM |
R4.00005: Side-chain mobility in the folded state of Myoglobin Heiko Lammert, Jose Onuchic We study the accessibility of alternative side-chain rotamer configurations in the native state of Myoglobin, using an all-atom structure-based model. From long, unbiased simulation trajectories we determine occupancies of rotameric states and also estimate configurational and vibrational entropies. Direct sampling of the full native-state dynamics, enabled by the simple model, reveals facilitation of side-chain motions by backbone dynamics. Correlations between different dihedral angles are quantified and prove to be weak. We confirm global trends in the mobilities of side-chains, following burial and also the chemical character of residues. Surface residues loose little configurational entropy upon folding; side-chains contribute significantly to the entropy of the folded state. Mobilities of buried side-chains vary strongly with temperature. At ambient temperature, individual side-chains in the core of the protein gain substantial access to alternative rotamers, with occupancies that are likely observable experimentally. Finally, the dynamics of buried side-chains may be linked to the internal pockets, available to ligand gas molecules in Myoglobin. [Preview Abstract] |
Thursday, March 16, 2017 9:24AM - 9:36AM |
R4.00006: Characterizing insertions in coiled coil proteins Nathan Schmidt, William DeGrado Coiled coils represent a common motif in proteins and figure largely in the assembly and dynamics required for diverse functions, including membrane fusion, signal transduction, and motors. A hallmark characteristic of coiled coils is a repeating 7-residue geometric and sequence motif. While there has been a great deal of attention given to the regular repeating structures within coiled coil proteins, much less is known about the structure and function of less regular regions in which one or more residues are inserted. Such insertions are often highly conserved and critical to interdomain communication in signaling proteins. Here we develop the ``accommodation index'' as a parameter that allows automatic detection and classification of insertions based on the three dimensional structure of a protein. Using bacterial histidine kinases as a test system, we show that sequence insertion defects in coiled coils can be accommodated structurally in different ways and used to create bifunctional switches for signal transduction. [Preview Abstract] |
Thursday, March 16, 2017 9:36AM - 9:48AM |
R4.00007: Estimates of Twisting and Bending Rigidities of Beta-Solenoid Proteins Using Molecular Dynamics Amanda Parker, Krishnakumar Ravikumar, Daniel Cox The use of beta-solenoid proteins as functionalizable, nano-scale, self-assembling molecular building blocks has many applications, including in templating the growth of wires or higher-dimensional structures. By understanding their mechanical strengths, we can more efficiently design the proteins for specific functions. We present a study of the mechanical properties of seven beta-solenoid proteins, where we use GROMACS molecular dynamics software to produce force/torque-displacement data, implement umbrella sampling of bending/twisting trajectories, produce PMFs, extract effective spring constants, and calculate rigidities, for two bending and two twisting directions for each protein. In particular, we examine the differences between computing the strength values from force/torque-displacement data alone and PMF data. In addition to the analysis of the methods, we report estimates for the flexural and torsional persistence lengths for each protein, which range from approximately 0.5-3.4 $\mu$m. [Preview Abstract] |
Thursday, March 16, 2017 9:48AM - 10:00AM |
R4.00008: Representing the Marginal Stability of Peptides in Coarse Grained Models Mehmet Sayar, Cahit Dalgicdir, Farhad Ramezanghorbani Tertiary structure of proteins is only marginally stable; such that the folded structure is separated from local minima by as little as 10 kcal/mol. In particular for intrinsically disordered peptides, this marginal stability is key to understanding their complex behavior. Bottom-up coarse grained (CG) models for proteins/peptides which rely on structural and/or thermodynamic reference data from experiments or all atom simulations inherently focus on the equilibrium structure and fail to capture the conformational dynamics of the molecule. In this study, we present a CG model for a synthetic peptide, LK, which successfully captures the conformational flexibility of the molecule in different environments. LK peptide is composed of leucine and lysine residues and displays a stark conformational transition from a degenerate conformation in dilute solution to a fully stable alpha-helix at macroscopic and molecular interfaces. In this study we demonstrate that by carefully combining atomistic references from both the unfolded and folded states, one can create a CG model that can represent not only the folded state, but also the conformational transitions that the peptide exhibits in response to changes in the environment. [Preview Abstract] |
Thursday, March 16, 2017 10:00AM - 10:12AM |
R4.00009: Computational Studies of Protein Core Mutations Jennifer Gaines, Lynne Regan, Corey O'Hern Predicting the effects of protein core mutations is a necessary first step in developing methods for computational protein design. Current computational methods have found limited success in predicting the changes in stability arising from protein core mutations. We implement a stereochemical plus hard-sphere (SHS) model for amino acid structure, which allows us to investigate in detail the physical mechanisms that give rise to differences in stability between natural and mutated protein cores. Here, we show that the SHS model can recapitulate the side chain dihedral angle distributions for amino acids in natural protein cores. In addition, we show that in many cases the SHS model can predict the experimentally measured changes in free energy due to mutations. In other cases, we find that add a term that favors packing fractions near those of natural protein cores, we are able to predict the stability of the mutated cores. These methods will be applicable to studying protein-protein interfaces and developing new protein-protein binding partners. [Preview Abstract] |
Thursday, March 16, 2017 10:12AM - 10:24AM |
R4.00010: Effect of salt entropy on protein solubility and Hofmeister series Yuba Dahal, Jeremy Schmit We present a theory of salt effects on protein solubility that accounts for salting-in, salting-out, and the Hofmeister series. We represent protein charge by the first order multipole expansion to include attractive and repulsive electrostatic interactions in the model. Our model also includes non-electrostatic protein-ion interactions, and ion-solvent interactions via an effective solvated ion radius. We find that the finite size of the ions has significant effects on the translational entropy of the salt, which accounts for the changes in the protein solubility. At low salt the dominant effect comes from the entropic cost of confining ions within the aggregate. At high concentrations the salt drives a depletion attraction that favors aggregation. Our theory explains the reversal in the Hofmeister series observed in lysozyme cloud point measurements and semi-quantitatively describes the solubility of lysozyme and chymosin crystals. [Preview Abstract] |
Thursday, March 16, 2017 10:24AM - 10:36AM |
R4.00011: Photo-reduction on the rupture of disulfide bonds and the related protein assembling Wei Wang It has been found that many proteins can self-assemble into nanoscale assemblies when they unfold or partially unfold under harsh conditions, such as low pH, high temperature, or the presence of denaturants, and so on. These nanoscale assemblies can have some applications such as the drug-delivery systems (DDSs). Here we report a study that a very physical way, the UV illumination, can be used to facilitate the formation of protein fibrils and nanoparticles under native conditions by breaking disulfide bonds in some disulfide-containing proteins. By controlling the intensity of UV light and the illumination time, we realized the preparation of self-assembly nanoparticles which encapsulate the anticancer drug doxorubicin (DOX) and can be used as the DDS for inhibiting the growth of tumor. The formation of fibrillary assemblies was also observed. The rupture of disulfide bonds through photo-reduction process due to the effect of tryptophan and tyrosine was studied, and the physical mechanism of the assembling of the related disulfide-containing proteins was also discussed. [Preview Abstract] |
Thursday, March 16, 2017 10:36AM - 10:48AM |
R4.00012: Effect of point mutations on the mechanics of enzymes Zahrasadat Alavi Using real time nano-rheology measurements, we have previously shown that the hydration layer of enzymes partially controls conformational dynamics. We perturbed the hydration layer of the enzyme Guanylate Kinase by adding small amounts of dimethyl sulfoxide (DMSO) and observed that the enzyme becomes more viscous. Here we explore the effect of point mutations on the mechanical response of the same molecule. We prepared point mutants where one Gly (the smallest amino-acid) is substituted at putative locations of high strain during enzymatic activity. In contrast to the surface perturbation, these internal changes of amino-acid sequence did not have a significant effect on the overall stiffness of the molecule, although in some cases the activity changes significantly. Using an enhanced detection system which takes advantage of surface plasmon resonance (SPR) we then studied the small changes in the mechanical response of the enzyme upon binding the different reactants and products (GMP, ATP, ADP and GDP for GK), for the different mutants. These small molecules typically modify the mechanical stiffness of the enzyme when binding to the active site. The goal here is to understand the significance of these changes. [Preview Abstract] |
Thursday, March 16, 2017 10:48AM - 11:00AM |
R4.00013: Modelling Tethered Enzymatic Reactions Citlali Solis Salas, Jesse Goyette, Nicola Coker-Gordon, Marcus Bridge, Samuel Isaacson, Jun Allard, Philip Maini, Omer Dushek Enzymatic reactions are key to cell functioning, and whilst much work has been done in protein interaction in cases where diffusion is possible, interactions of tethered proteins are poorly understood. Yet, because of the large role cell membranes play in enzymatic reactions, several reactions may take place where one of the proteins is bound to a fixed point in space. We develop a model to characterize tethered signalling between the phosphatase SHP-1 interacting with a tethered, phosphorylated protein. We compare our model to experimental data obtained using surface plasmon resonance (SPR). We show that a single SPR experiment recovers 5 independent biophysical/biochemical constants. We also compare the results between a three dimensional model and a two dimensional model. The work gives the opportunity to use known techniques to learn more about signalling processes, and new insights into how enzyme tethering alters cellular signalling. [Preview Abstract] |
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