The Mechanical Mechanism To Regulate Antimicrobial Ctivity Of Antimicrobial Peptides

Antimicrobial peptides (AMPs) are ancient players in innate immunity. The number ofAMPs which have been found or predicted is over1200. AMPs are variously active against awide range of pathogens, such as gram-positive bacteria, gram-negative bacteria, fungi andprotozoa. The subsequent and fascinating discovery is that AMPs can function as the regulatorof both innate and adaptive immunity. They are therefore proposed as one of the most likelysubstitutes for common antibiotics, to confront an increasingly serious threat to human healthcaused by antibiotic-resistant bacterial infection. AMPs act very fast, have various targets, andare not easy to develop the bacterial resisitance. AMPs have stimulated large interests.It is believed that the antimicrobial activity is related to structural parameters, such as thepeptide conformation, charge, hydrophobicity, amphipathicity, and polar angle. These featuresare important to the antimicrobial action. However, flexibility acts on this process doubtlessly.The study here focused on the flexibility of the AMPs, and explored the structure-activityrelationship and the antimicrobial mechanism. We have estabilished the procedures ofderiving the spring constants of small molecules like AMPs through steered moleculardynamics simulation, and the mechanical properties of HP(2-20) and its four analogues haveobtained already. The antimicrobial activity increased with the rigidity for HP(2-20) and itsanalogues, which is a new structure-activity relationship based on rigidity for AMPs. Toinvestigate the antimicrobial mechanism, the AMPs/membrane systems were built bymolecular dynamics simulation. AMPs limited the movements of the lipids in the regionwhich AMPs interact with on the membrane. The membrane would become nonuniform afterthe AMPs binding to it.Then finite element analysis was used in this study to explore throughly the effects ofAMPs with different rigidity. The values and distributions of stress, strain, and strain energydensity were examined. The results showed that the stress concentrations appeared on andaround the interfaces between the terminals and the membrane, and the stress concentrationpoints appeared on the four vertexs of the AMPs. The strains had leaps on the interfaces, andthe maximum of strain energy density also appeared on the four vertexs of the AMPs. Themembrane would be torn easily on these regions under the environmental thermal motions,which might lead the membrane to be collapsed, or other free AMPs to insert into themembrane. There may be a mechanical mechanism to regulate the AMPs' action.We further developed another simple method based on B-factor to evaluate the flexibilityof nine different AMPs groups. Two direct connections between flexibility and activity were revealed in two types of AMPs groups respectively. The flexibility expressed as a promotionof the antimicrobial activity in the case of a low-level flexibility. On the other hand, theantimicrobial activity decreased with the increase of flexibility when flexibility kept onincreasing and exceeded the dividing point. Therefore, the effects of flexibility on theantimicrobial activity are complicated, which need to consider the balance between flexibilityand stability, and the mechanical mechanism.In this study, the evaluated methods of flexibility of short peptides like AMPs have beendeveloped. A new structure-activity based on flexibility has been revealed, which is a clue todevelop a new activity design-method for AMPs drugs. Besides, a mechanical mechanism onAMPs' action has been proposed, which provides a new perspective for AMPs researches.