The design of a peptide sequence to inhibit HIV replication: a search algorithm combining Monte Carlo and self-consistent mean field techniques

Abstract

We developed a search algorithm combining Monte Carlo (MC) and self-consistent mean field techniques to evolve a peptide sequence that has good binding capability to the anticodon stem and loop (ASL) of human lysine tRNA species, tRNA(Lys3), with the ultimate purpose of breaking the replication cycle of human immunodeficiency virus-1. The starting point is the 15-amino-acid sequence, RVTHHAFLGAHRTVG, found experimentally by Agris and co-workers to bind selectively to hypermodified tRNA(Lys3). The peptide backbone conformation is determined via atomistic simulation of the peptide-ASL(Lys3) complex and then held fixed throughout the search. The proportion of amino acids of various types (hydrophobic, polar, charged, etc.) is varied to mimic different peptide hydration properties. Three different sets of hydration properties were examined in the search algorithm to see how this affects evolution to the best-binding peptide sequences. Certain amino acids are commonly found at fixed sites for all three hydration states, some necessary for binding affinity and some necessary for binding specificity. Analysis of the binding structure and the various contributions to the binding energy shows that: 1) two hydrophilic residues (asparagine at site 11 and the cysteine at site 12) "recognize" the ASL(Lys3) due to the VDW energy, and thereby contribute to its binding specificity and 2) the positively charged arginines at sites 4 and 13 preferentially attract the negatively charged sugar rings and the phosphate linkages, and thereby contribute to the binding affinity.

Introducing folding stability into the score function for computational design of RNA‐binding peptides boosts the probability of success

“…Examination of the energies (Table ) shows that the five complexes exhibit little change in the GBSUR energy, a medium‐size change in the intermolecular VDW energy and TS energy, and a large change in the intermolecular ELE + EGB energy. In our prior work on recognition mechanisms between peptide and RNA, we have found that the intermolecular ELE + EGB energy is responsible for the binding affinity and the intermolecular VDW energy is responsible for the binding specificity. Our simulation reveals that adding a peptide stability term with a weighting of λ = 0.010 to the score function greatly enhances the binding affinity between peptide and ASL Lys3 due to the notable decrease in the ELE + EGB energy.…”

“…In previous papers, we developed a hybrid search algorithm combining Monte Carlo (MC), Self‐consistent mean field theory (SCMF) and the concerted rotation move (CONROT) techniques to evolve peptide sequences that recognize and bind to ASL Lys3 . The advantage of our hybrid search algorithm is that it allows us to iterate between sequence mutations and conformation changes, thereby optimizing the peptides simultaneously in sequence space and in conformation space during the evolution process.…”

“…We repeat the aforementioned evolution steps hundreds of thousands of times with the aim of discovering potential peptide sequence candidates. A detailed description of our search algorithm can be found in our previous papers …”

Adding energy minimization strategy to peptide‐design algorithm enables better search for RNA‐binding peptides: Redesigned λ N peptide binds boxB RNA

“…The conformation of boxB RNA and the backbone conformation of the peptide are fixed during sequence evolutions. Unlike our previous algorithm [21], the new algorithm does not need the self-consistent mean field technique to determine appropriate rotamer combinations from a library of fixed sidechain configurations. Instead we add an energy minimization step to determine optimal sidechain configuration for the amino acid repacking.…”

“…DPP-Fe cofactor. In our previous work [21], a search algorithm combining MC and SCMF techniques was developed to evolve peptide sequences that have good binding capability to the anticodon stem and loop (ASL) of human lysine tRNA species, viz . ASL Lys3 , with the ultimate purpose of breaking the replication cycle of human immunodeficiency virus-1.…”