Abstract
Disulfide-rich peptides isolated from the venom of arthropods and marine animals are a rich source of potent and selective modulators of ion channels. This makes these peptides valuable lead molecules for the development of new drugs to treat neurological disorders. Consequently, much effort goes into understanding their mechanism of action. This paper presents an overview of how molecular simulations have been used to study the interactions of disulfide-rich venom peptides with ion channels and membranes. The review is focused on the use of docking, molecular dynamics simulations, and free energy calculations to (i) predict the structure of peptide-channel complexes; (ii) calculate binding free energies including the effect of peptide modifications; and (iii) study the membrane-binding properties of disulfide-rich venom peptides. The review concludes with a summary and outlook.
Highlights
Thhee vveennoommoof faratrhtrhorpoopdosd(se.(ge.,gs.,psidpeidrse,rssc,osrcpoiropniso,nasn,dancedntciepnetdipese)daensd) amnadrimnearainniemaanlsim(ea.gls.,naerse) aareriachricshousrocuercoef obfioblioogloicgaicllayllyacaticvtievemmoloelceucluelse.s.AA major component of these venoms are disulfifide-rich peptides, referred to as toxins
Many of the simulation techniques described in this review are not suitable for screening approaches typically used during early stages of drug discovery. They are more applicable to characterising a small number of peptides during later-stage lead optimisation or to study model systems for understanding the fundamental processes that govern the binding of peptides to ion channels and membranes
Free energy calculations are used to estimate the effect of chemical modifications in the peptide on its binding affinity. This is often obtained from free energy perturbation (FEP) or end-point methods such as the molecular mechanics Poisson-Boltzmann or generalized born surface area method (MM/PBSA and MM/GBSA, respectively) [86,87,88,89,90]
Summary
Thhee vveennoommoof faratrhtrhorpoopdosd(se.(ge.,gs.,psidpeidrse,rssc,osrcpoiropniso,nasn,dancedntciepnetdipese)daensd) amnadrimnearainniemaanlsim(ea.gls., (ceo.nge., scnoanielss,njaeillsy,fijeslhlyesfi,sahneds, asenad asneaemanoenmeso)naerse) aareriachricshousrocuercoef obfioblioogloicgaicllayllyacaticvtievemmoloelceucluelse.s.AA major component of these venoms are disulfifide-rich peptides, referred to as toxins. Most simulation studies of disulfide-rich venom peptides have focused on understanding the interactions of peptides bound to voltage-gated NaV and KV channels [14,16,17] as well as ASICs [18,19,20,21] (see Figure 2). Many of the simulation techniques described in this review are not (yet) suitable for screening approaches typically used during early stages of drug discovery They are more applicable to characterising a small number of peptides during later-stage lead optimisation or to study model systems for understanding the fundamental processes that govern the binding of peptides to ion channels and membranes. The reader should be aware that there are other computational methods used to study venom peptides that are not discussed here (e.g., QSAR, knowledge-based potential methods for peptide-channel docking, or Brownian dynamics simulations [30,31,32])
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