Biology subjects

Perahia, D.

Publications and source records attributed to Perahia, D..

3 recordsLinked to original sources

bioRxiv2022

Adaptive collective motions: a hybrid method to improve conformational sampling with molecular dynamics and normal modes

Protein function is closely related to its structure and dynamics. Due to its large number of degrees of freedom, proteins adopt a large number of conformations, which describe a highly complex potential energy landscape. Considering the huge ensemble of conformations in dynamic equilibrium in solution, detailed investigation of proteins dynamics is extremely costly. Therefore, a significant number of different methods have emerged in order to improve the conformational sampling of biomolecules. One of these methods is Molecular Dynamics with excited Normal Modes (MDeNM) in which normal modes are used as collective variables in molecular dynamics. Here, we present a new implementation of the MDeNM method that allows a continuously controlled kinetic excitation energy in the normal mode space, while taking into account the natural constraints imposed either by the structure or the environment. These implementations prevent unphysical structural distortions. We tested the new approach on bacteriophages T4 lysozyme, Gallus gallus hen egg-white lysozyme and Staphylococcus aureus membrane-bound transglycosylase. Our results showed that the new approach outperformed free MD sampling and preserved the structural features comparatively to the original MDeNM approach. We also observed that by adaptively changing the excitation direction during calculations, proteins follow new transition paths preventing structural distortions.

biophysics↗

bioRxiv2021

Unveiling Mutation Effects on the Structural Dynamics of the Main Protease from SARS-CoV-2 with Hybrid Simulation Methods

The main protease of SARS-CoV-2 (called Mpro or 3CLpro) is essential for processing polyproteins encoded by viral RNA. Macromolecules adopt several favored conformations in solution depending on their structure and shape, determining their dynamics and function. Integrated methods combining the lowest-frequency movements obtained by Normal Mode Analysis (NMA), and the faster movements from Molecular Dynamics (MD), and data from biophysical techniques, are necessary to establish the correlation between complex structural dynamics of macromolecules and their function. In this article, we used a hybrid simulation method to sample the conformational space to characterize the structural dynamics and global motions of WT SARS-CoV-2 Mpro and 48 mutants, including several mutations that appear in P.1, B.1.1.7, B.1.351, B.1.525 and B.1.429+B.1.427 variants. Integrated Hybrid methods combining NMA and MD have been useful to study the correlation between the complex structural dynamics of macromolecules and their functioning mechanisms. Here, we applied this hybrid approach to elucidate the effects of mutation in the structural dynamics of SARS-CoV-2 Mpro, considering their flexibility, solvent accessible surface area analyses, global movements, and catalytic dyad distance. Furthermore, some mutants showed significant changes in their structural dynamics and conformation, which could lead to distinct functional properties. HighlightsO_LISingle surface mutations lead to changes in Mpro structural dynamics. C_LIO_LIMutants can be more stable than WT according to the structural dynamics properties. C_LIO_LIMpromutants can present a distinct functionality in relation to the wild-type. C_LIO_LIPotential viral markers for more pathogenic or transmissible SARS-CoV-2 variants. C_LI

biophysics↗

bioRxiv2019

Unveiling functional motions based on point mutations in biased signaling systems: A normal mode study on Nerve Growth Factor bound to TrkA

Many receptors elicit signal transduction by activating multiple intracellular pathways. This transduction may be triggered by a nonspecific ligand, which simultaneously activates all receptors signaling paths. In addition, the binding of a biased ligand preferentially elicits one path over another, in a process called biased signaling. Identifying the functional motions related to each one of these distinct pathways have direct impact in the development of new efficient and specific drugs. Here we show how to detect functional motions considering the case of the NGF/TrkA-Ig2 complex. TrkA receptors activation mediated by NGF depends on specific structural motions that trigger neuronal growth, development and survival in nervous system. R221W mutation in the ngf gene impairs the nociceptive signaling. Here we show the wide spread structural effects of this mutation in the NGF/TrkA-Ig2 complex, leading to the deletion of collective motions important to TrkA activation of nociceptive signaling. Our results suggest that subtle changes in the interaction network within neurotrophic factors due to the point mutation are sufficient to inhibit necessary conformational changes for TrkA receptors activation. The methodological approach presented in this article based conjunctively on normal mode analysis and the experimentally observed functional alterations due to point mutations provides an essential tool for unveiling the structural changes and motions related to the disease, that in turn could be important for a drug design study.

bioinformatics↗