Electrostatics in the Stability and Misfolding of the Prion Protein: Salt Bridges, Self-Energy, and Solvation

Electrostatics in the Stability and Misfolding of the Prion Protein: Salt Bridges, Self-Energy, and Solvation Will Guest1, Neil Cashman1,3, and Steven Plotkin2,3 November 8, 2018 Submitted to Biochemistry and Cell Biology CSBMCB Special Issue on Protein Misfolding 1Brain Research Centre, University of British Columbia, V6T 2B5 2Department of Physics and Astronomy, University of British Columbia, V6T 1Z1 3Corresponding authors (Email: neil.cashman@vch.ca, steve@physics.ubc.ca, Phone: 1-604-822-2135, 1-604- 822-8813) 1 arXiv:1004.1590v1 [cond-mat.soft] 9 Apr 2010 Abstract Using a recently developed mesoscopic theory of protein dielectrics, we have calculated the salt bridge energies, total residue electrostatic potential energies, and transfer energies into a low dielectric amyloid- like phase for 12 species and mutants of the prion protein. Salt bridges and self energies play key roles in stabilizing secondary and tertiary structural elements of the prion protein. The total electrostatic potential energy of each residue was found to be invariably stabilizing. Residues frequently found to be mutated in familial prion disease were among those with the largest electrostatic energies. The large barrier to charged group desolvation imposes regional constraints on involvement of the prion protein in an amyloid aggregate, resulting in an electrostatic amyloid recruitment profile that favours regions of sequence between alpha helix 1 and beta strand 2, the middles of helices 2 and 3, and the region N-terminal to alpha helix 1. We found that the stabilization due to salt bridges is minimal among the proteins studied for disease-susceptible human mutants of prion protein. Keywords: Salt bridge, prion, protein misfolding, protein electrostatics 2 Introduction Misfolded prion protein is the causative agent for a unique category of human and animal neurodegenerative diseases characterized by progressive dementia, ataxia, and death within months of onset (Prusiner 1998). These include Creutzfeldt-Jakob disease (CJD), fatal familial insomnia, and Gerstmann-Str¨aussler-Scheinker syndrome in humans, bovine spongiform encephalopathy in cattle, scrapie in sheep, and chronic wasting disease in cervids. Unlike other infectious conditions that are transmitted by conventional microbes, the material responsible for propagation of prion diseases consists of an abnormally folded conformer of an endogenous protein, possibly in complex with host nucleic acids or sulfated glycans (Caughey et al. 2009). Soluble, natively-folded monomers of the prion protein (known as PrPC) may adopt an aggregated protease- resistant conformation known as PrPScthat is capable of recruiting additional monomers of PrPCand inducing them to misfold in a process of template-directed conversion. This results in ordered multimers of prion protein that, when fractured, act as additional seeds to propagate the misfold through the reservoir of PrPC present in brain. Although the conversion process may be initiated by an infectious inoculum of PrPSc, it may also arise spontaneously or due to mutations in the gene coding for PrP that predispose to misfolding. Structurally, PrPC is a glycophosphatidylinositol-anchored glycoprotein of 232 amino acids comprising an N-terminal unstructured domain and a C-terminal structured domain of 3 α-helices (hereafter referred to as α1, α2, and α3 in order) and a short two-stranded antiparallel β-sheet (made of strands β1 and β2), while PrPSc has substantially enriched β content speculated to form a stacked β-helix (Govaerts et al. 2004) or extended β-sheet (Cobb et al. 2007) conformation in the amyloid fibril. At a molecular level PrP misfolding is a physico-chemical process, with the propensity to misfold deter- mined by the free energy difference between folded and misfolded states and the magnitude of the energy barrier separating them. As in any protein system, electrostatic effects make significant contributions to the energies of the various states and take two forms: salt bridge energy due to spatial proximity of charged groups within the native protein, and solvation/self energy due to field energy storage in the ambient protein and water dielectric media. A priori, it is expected that electrostatic effects generally favour the well-solvated monomeric PrPC over the more hydrophobic amyloid PrPSc, since formation of PrPSc necessitates disruption of salt bridges in the native structure (although this may be compensated for by the formation of alternative salt bridges in PrPSc) and transfer of some charged groups into an environment of lower permittivity, both of which are energetically costly. However, these penalties on formation of PrPSc are counterbalanced by hydro- gen bonding, hydrophobic, and possibly entropic contributions that favour the amyloid form (Tsemekhman et al. 2007). Regional variation in the electrostatic transfer energy to water and amyloid may be useful in 3 predicting participation in the amyloid core of PrPSc

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