期刊
JOURNAL OF COMPUTATIONAL CHEMISTRY
卷 42, 期 25, 页码 1809-1816出版社
WILEY
DOI: 10.1002/jcc.26719
关键词
conformational sampling; constant pH; molecular dynamics; pHLIP; point mutations
资金
- National Institutes of Health [GMI20676]
pH-Low Insertion Peptide (pHLIP) is a membrane-active peptide that can fold into a transmembrane alpha-helix under acidification, potentially serving as a drug vector for diseases characterized by acidosis. Molecular dynamics simulations showed that the addition of ions can reduce the pKa of acidic residues in pHLIP, with the variant P20G exhibiting higher helicity and compactness. Sodium cations tend to localize to the C-terminus of the peptide, and the salt bridge between R11 and D14 is favored, especially in pHLIP at 150 mM NaCl.
The pH-Low Insertion Peptide (pHLIP) is a membrane-active peptide that spontaneously folds into a transmembrane alpha-helix upon acidification. This activity enables pHLIP to potentially act as a vector for drugs related to diseases characterized by acidosis such as cancer or heart ischemia. Presently, due to aggregation-based effects, formulations of pHLIP are only viable at near-mu M concentrations. In addition, since most of pHLIP's measurable qualities involve a membrane, probing the details of pHLIP in the interstitial region is difficult. In attempts to shed light on these issues, we performed constant pH molecular dynamics simulations on pHLIP as well as P20G, a variant with increased helicity, in solution at 0 and 150 mM NaCl over a broad range of pHs. In general, the addition of ions reduced the effective pK(a) of the acidic residues in pHLIP. P20G exhibits a higher helicity than pHLIP in general and is more compact than pHLIP at pH values under 4. In terms of charge effects, sodium cations localized predominantly to the C-terminus of the peptide with a high density of acidic residues. Additionally, the salt bridge between R11 and D14 is by far the most favored and particularly so with pHLIP at 150 mM NaCl. We expect that this approach will be a valuable tool to screen variants of pHLIP for favorable properties in solution, an aspect of pHLIP design that to this point has largely been neglected.
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