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