Conformational Stability and Pathogenic Misfolding of the Integral Membrane Protein PMP22

Conformational Stability and Pathogenic Misfolding of the Integral Membrane Protein PMP22
Schlebach et al. 2015 (Sanders Lab - Vanderbilt) - JACS

• Understanding of reactions that limit assembly and trafficking of membrane proteins remains superficial
• Assess relationship between stability of an MP and degree to which its retained by the quality control system
• Looked at 12 variants of PMP22 - linked to charcot-marie-tooth disease (CMT)
• Influence ZnII mediated folding proportional to reduction in trafficking efficiency
• Mutations important for energetics of PMP22 folding and a molecular basis for CMT

Lipid Membrane Deformation Accompanied by Disk-to-Ring Shape Transition of Cholesterol-Rich Domains

Lipid Membrane Deformation Accompanied by Disk-to-Ring Shape Transition of Cholesterol-Rich Domains
Ryu et al. 2015 - JACS

• Biological membranes subject to lipid- and protein-mediated deformations
• Observe disk-to-ring shape morpho chemical transition of a membrane without constraints
• Raft transition triggered by change in composition 
• Flat membranes can become curved by dynamic changes in local chemical conformation and shape changes in cholesterol rich regions. 

Hijacked then lost in translation: the plight of the recombinant host cell in membrane protein structural biology projects

Hijacked then lost in translation: the plight of the recombinant host cell in membrane protein structural biology projects
Bill & von der Haar, 2015 - COSB

• "High quality protein" required for membrane protein crystallography
• Still difficult to obtain recombinant membrane protein in sufficient yield
• Use recombinant host cells - "cell factory" 
• Typically makes mutations to increase: 
• Protein yield
• protein stability
• Crystallization propensity

*Good review for MP experimental techniques

Multidimensional persistence in biomolecular data

Multidimensional persistence in biomolecular data
Xia & Wei et al. 2015 (JCC)

• Persistent homology - technique used to simplify big data - especially for biomolecular data
• Important for bridging the gap between data geometry & topology
• Two families of persistence: 
• Pseudo-multidimensional persistence: repeated application of filters to high-dimensional data such as MD trajectories
• Multi-scale multidimensional persistence: isotropic and anisotropic scales that create new spaces

**Way off topic - but good to know about data processing methods

Arginine in membranes: connection between molecular dynamics simulations and translocon-mediated insertion experiments

Arginine in membranes: connection between molecular dynamics simulations and translocon-mediated insertion experiments
Schow et al. 2011 (G. von Heijne, White, Tobias) - Journal of Membrane Biology

• Experiments disagree with computation: MD simulations find energetic cost of inserting arginine is an order of magnitude greater than in molecular biology experiments
• MD simulation of guanidinium groups + helices containing Arg at different positions along the helix
• Can reduce discrepancy by considering free energy difference between arginine at the interface
• Suggests arg snorkels to the interface prevents it from residing in the bilayer center
• Challenge with MD - measures water-to-bilayer free energies whereas molecular biology measures partitioning from translocon to bilayer: what is the relationship here? 
• Might not be a thermodynamic cycle connecting the two paths (transolocon to bilayer vs. water to bilayer). 

Thermodynamic measurements of bilayer insertion of a single transmembrane helix chaperoned by fluorinated surfactants

Thermodynamic measurements of bilayer insertion of a single transmembrane helix chaperoned by fluorinated surfactants
Kyrychenko et al. 2012 (Alexey Ladokhin) - Journal of Molecular Biology

• Uses fluorinated surfactants to overcome peptide aggregation outside the membrane bilayer
• Study surfactant-chaperoned insertion into POPC vesicles with two WALP peptides: WALP23 and WALP27
• Meausres -9.0 + 0.1 and -10.0 + 0.1 kcal/mol for WALP23 and WALP27 respectively
• CD measurements confirm helicity
• Calculates 4-residue LALA segment in a helix costs ~1 kCal/mol to insert

Lipid headgroups modulate membrane insertion of PHLIP peptide

Lipid headgroups modulate membrane insertion of PHLIP peptide
Kyrychenko et al. 2015 (Alexey Ladokhin) - Biophysical Journal

• pH Low insertion peptide (pHLIP) important tool for visualization & drug delivery
• Exists in three states: unfolded and soluble in water at neutral pH, unfolded and bound to surface of a PC membrane at neutral pH, and inserted across the membrane as an alpha helix at low pH
• Given anionic lipids, cholesterol or PE eliminates membrane binding at neutral pH
• pKa for insertion is increased with increasing anionic lipid content
• Suggests electrostatics at the interface modulate protonation important for insertion

Monte carlo vs. molecular dynamics for all-atom polypeptide folding simulations

Monte carlo vs. molecular dynamics for all-atom polypeptide folding simulations
Ulmschneider, Ulmshnedier & Di Nola, 2006 - J. Phys. Chem. B

• Compared efficient MC to all-atom MD in folding of small polypeptides
• Algorithm "concerted rotations with flexible bond angles" (CRA) can successfully find the native state
• MC folds the native state 2-2.5 times faster than the MD runs
• Thermodynamic and dynamic properties can be obtained by both methods
• 1 MD integration step of 2fs corresponds to 1 MC scan
• MC important in combination with replica exchange methods

Membrane protein properties revealed through data-rich electrostatics calculations

Membrane protein properties revealed through data-rich electrostatics calculations
Marcoline, Bethel et al. 2015 (Grabe Lab - UCSF) - Structure (Cell)

• Electrostatic characteristics important for ion channel selectivity and stability of charged membrane-spanning segments
• PB equation gold standard for protein electrostatics - APBSmem enables this for membrane proteins
• Describes large advances to APBSmem including per-residue energy decmposition, automated system setup, membrane-induced pKa shifts, non-polar energies, and command line access
• Survey of 1,614 membrane proteins of known structure and investigation of ion channel TRPV1
• Curates a large list of residues with electrostatic penalties for membrane embedding, possibly revealing important functional information

MemProtMD: Automated insertion of membrane protein structures into explicit lipid membranes

MemProtMD: Automated insertion of membrane protein structures into explicit lipid membranes

Stansfeld et al. 2015 (Sansom Lab) - Structure (Cell)

• Membrane proteins structures often resolved in the absence of their native lipid environment
• Automated method to identify membrane proteins in the PDB and insert into an explicit lipid bilayer
• First performed at the CG level, then backtrace to the all-atom level
• Can analyze recently determined protein structures for locations in the membrane, lipid-protein interactions and functional implications

A general computational approach for repeat protein design

A general computational approach for repeat protein design
Parmeggiani, Huang et al. 2015 (Baker Lab) - Journal of Molecular Biology

• Repeat proteins useful as binding reagents or biomaterials for various applications
• General method for building idealized repeats - combines sequence & structural information with de novo protein design calculations
• Idealized designs from six protein families were experimentally characterized: 80% souble, 40% folded and monomeric with high thermal stability
• Crystal structures are within 1Å of designs
• General, reliable and fast generation of stable, modular repeat scaffolds

Graphical Abstract from paper

BCL::SAXS: GPU accelerated Debye method for computation of small angle X-ray scattering profiles

BCL::SAXS: GPU accelerated Debye method for computation of small angle X-ray scattering profiles
Putnam et al. 2015 - Proteins: Structure, Function, Bioinformatics
(Paper from Meiler Lab)

• SAXS: Small angle x-ray scattering used to characterize structures in solution
• Algorithm that can replicate SAXS profiles 
• Abilities of the algorithm: 
• Represent complete models
• Models with approximated side chain coordinates
• Models with approximated side chain and loop region coordinates
• Algorithm can identify the correct SAXS profile and protein topology with 99% accuracy (ROC Area)
• Can be used to as a filter to exclude models with large structural differences from the native

Equilibrium Transitions between side chain conformations in leucine and isoleucine

Equilibrium Transitions between side chain conformations in leucine and isoleucine
Caballero et al. 2015 - Proteins: Structure, function, bioinformatics

• Difficult to understand the probabilities of amino acids to adopt specific side chain conformations
• Used Langevin Dynamics simulations of Isoleucine and Leucine dipeptide mimetics to determine the relative populations of side chain dihedral angles
• Determined relative populations of X1, X2 as a function of dihedral angles phi/psi
• Proposes a mechanism for conversion between different conformations: some conversions more frequent than others
• Used single steric models to investigate

Post-expression strategies for structural investigations of membrane proteins

Post-expression strategies for structural investigations of membrane proteins
Columbus, 2015 - COSB

• Four techniques used to facilitate MP expression: 
• limited proteolysis - removes flexible regions
• Deglycosylation - removes heterogeneous post-translational modifications
• cysteine alkylation - prevents disulfide dimers and higher order oligomers
• lysine methylation 
• Useful for determining more than 40 MP structures

(Figure 1 from Review)