Extended Concerted Rotation Technique Enhances the Sampling Efficiency of the Computational Peptide-Design Algorithm

Abstract

To enhance the sampling efficiency of our computational peptide-design algorithm in conformational space, the concerted rotation (CONROT) technique is extended to enable larger conformational perturbations of peptide chains. This allows us to make relatively large peptide conformation changes during the process of designing peptide sequences to bind with high affinity to a specific target. Searches conducted using the new algorithm identified six potential λ N(2-22) peptide variants, called B1-B6, which bind to boxB RNA with high affinity. The results of explicit-solvent atomistic molecular dynamics simulations revealed that four of the evolved peptides, viz. B1, B2, B3, and B5, are excellent candidate binders to the target boxB RNA as they have lower binding free energies than the original λ N(2-22) peptide. Three of the four peptides, B2, B3, and B5, result from searches that contain both sequence and conformation changes, indicating that adding backbone motif changes to the peptide-design algorithm improves its performance considerably.

De novo design of peptides that coassemble into β sheet–based nanofibrils

“…The key advance is a Monte Carlo (MC)-type peptide coassembly design (PepCAD) algorithm that is used for de novo design of charge-complementary peptide pairs. This method is a logical extension of our previously developed peptide binding design (PepBD) algorithm (28)(29)(30)(31)(32) that we applied to design peptide binders to biomolecular targets with exceptional affinities (33)(34)(35). Lead compounds from the computational search are subjected to discontinuous molecular dynamics (DMD) simulations combined with the knowledge-based PRIME20 force field (36)(37)(38)(39)(40) to examine the coassembly kinetics of the in silico discovered peptide pairs and the self-association of each peptide species when alone.…”

In Silico Discovery and Validation of Neuropeptide-Y-Binding Peptides for Sensors

“…Using the implicit-solvent molecular mechanics/generalized Born surface area (MM/GBSA) approach with the variable internal dielectric constant model, we postanalyze the last 10 ns simulation trajectories of all of the peptide–NPY complexes to calculate their binding free energies. Details of the computational procedures can be found in our previous work. − …”

“…We have been working to develop fast and automated methods to design peptides with exceptional binding affinities for protein or RNA targets. − Our computational algorithm uses atomistic force fields rather than knowledge-based information to design peptide sequences; this enables us to design high-affinity binding peptides to targets that have no known binders available in the protein data bank. In recent work, we used the computational algorithm to successfully evolve a 12-mer peptide-based BRE for the detection of cardiac event biomarker protein troponin I (cTnI) .…”

Advancing Peptide-Based Biorecognition Elements for Biosensors Using in-Silico Evolution

“…In-silico peptide evolution starts from a target complex identified from modeling by using I-TASSER to calculate the solution structure of cTnI and ZDOCK to identify potential peptide binding sites. Replica-exchange molecular dynamics with the AMBER force field was used to determine binding sites that are amenable to binding with peptides attached to gold surfaces. , The optimized peptide sequence was obtained using Monte Carlo-based software written at North Carolina State University, as previously described. , Molecular dynamics simulations were used to evaluate the thermodynamics of the bound peptides using the AMBER force field with TIP3P water and chloride ions to neutralize the system. Additional details are provided in the Supporting Information.…”

“…23,24 The optimized peptide sequence was obtained using Monte Carlobased software written at North Carolina State University, as previously described. 25,26 Molecular dynamics simulations were used to evaluate the thermodynamics of the bound peptides using the AMBER force field with TIP3P water and chloride ions to neutralize the system. Additional details are provided in the Supporting Information.…”