Ponente
Descripción
Alejandro A. P. Russo, Luis Albrizzi, Christian E. Schaerer, José Colbes, Santiago Di Lella, Carlos A. Brizuela
Cell-penetrating peptides (CPPs) are a class of biomolecules capable of crossing eukaryotic cell membranes and transporting bioactive molecules into the cell. Due to their biotechnological and therapeutic potential, the computational identification of CPPs has received increasing attention (Guidotti, G. et al., Trends Pharmacol. Sci. 38, 406–424, 2017). However, most current CPPs identification methods are based primarily on static sequence or structure characteristics, which can generate a significant number of false positives.
In this work, we investigate whether the dynamic response of peptides to an external electric field can reveal systematic differences between penetrating peptides (CPPs) and non-penetrating peptides (NCPPs). The physical motivation arises from studies showing that electric fields of comparable magnitude to those present at biological interfaces can induce significant structural changes in biomolecules (De Biase, P.M. et al., Biophys. J. 96, 4390–4402, 2009).
Molecular dynamics simulations will be performed using the AMBER package (Case, D.A. et al., J. Comput. Chem. 26, 1668–1688, 2005). In this context, a uniform electric field $E$ is applied to the molecular system. The force exerted on atom i with partial charge $q_i$ is given by
\begin{equation}
\mathbf{F}_i = q_i \mathbf{E}
\end{equation}
The potential energy associated with the interaction of the electric field with the system is expressed as
\begin{equation}
U = - \sum_{i=1}^{N} q_i \mathbf{r}_i \cdot \mathbf{E} = - \mu \cdot \mathbf{E}
\end{equation}
where $\mu$ represents the total dipole moment of the system (De Biase, P.M. et al., 2009).
A curated set of penetrating and non-penetrating peptides is presented, whose initial structures were obtained by prediction using ESMFold (Lin, Z. et al., Science 379, 1015–1022, 2023). Each peptide is simulated under two experimental scenarios: an aqueous solution representing a system without external disturbance, and an aqueous solution with the application of a uniform electric field $E$. All calculations involving electric fields were performed with an intensity of 25 $mV \textup{Å}^{-1}$, which is approximately one quarter of the estimated intensity for a fully saturated phosphatidylcholine membrane model (De Biase, P.M. et al., 2009).
The trajectories obtained through molecular dynamics are analyzed to extract structural and dynamic descriptors, such as conformational fluctuations, structural reorganization, and intramolecular interaction stability.
The set of penetrating peptides (CPPs) analyzed consists of ChenCPP1 (AAVALLPAVLLALLAKNNLKDCGLF), ChenCPP2 (AAVALLPAVLLALLAKNNLKECGLY), ChenCPP3 (AAVALLPAVLLALLAPVQRKQKLMP), ChenCPP4 (AAVALLPAVLLALLAVTDQLGEDFFAVDLEAFLQEFGLLPEKE), and ChenCPP5 (AAVLLPVLLAAP). The non-penetrating peptides (NCPPs) analyzed consist of ChenNCPP1 (AGCKNFFWKTFTSC), ChenNCPP2 (AHALCLTERQIKSNRRMKWKKEN), ChenNCPP3 (CYFQNCPRG), ChenNCPP4 (DFDMLRCMLGRVYRPCWQV), and ChenNCPP5 (EILLPNNYNAYESYKYPGMFIALSK).
The central hypothesis of this study is that CPPs exhibit a characteristic dynamic response to electrical disturbances, reflecting physical mechanisms associated with their interaction with cell membranes. If this hypothesis is confirmed, the dynamics induced by the electric field could be used as an additional criterion to improve the accuracy of current methods for predicting CPPs.
Acknowledgment
The authors acknowledge the support provided by the FEEI-CONACYT-PROCIENCIA project ESTR01-23 ARASY.