Unfolding stabilities of two structurally similar proteins as probed by temperature-induced and force-induced molecular dynamics simulations

Gorai, Biswajit; Prabhavadhni, Arasu; Sivaraman, Thirunavukkarasu

doi:10.1080/07391102.2014.986668

Cited by 6 publications

(2 citation statements)

References 57 publications

(67 reference statements)

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“…Short-length (nanoseconds) MD simulations of CTs in water were performed studying toxin behavior in different environments (water, detergent micelles), 20 the existence of tightly bound waters in the loop II region 21 and the unfolding stability of CTs at various temperatures. 22 Deciphering the structure−function relationships for CTs is especially important and interesting since these proteins have a very similar and stable spatial structure, although their activity can seriously vary. In contrast to many other membrane-targeting polypeptides (e.g., linear antimicrobials 23 ) CTs do not undergo significant conformational rearrangements upon binding to membranes.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Most of them have focused on the modeling of the toxins’ interaction with implicit or explicit model membranes , without detailed analysis of the observed conformational states of proteins. Short-length (nanoseconds) MD simulations of CTs in water were performed studying toxin behavior in different environments (water, detergent micelles), the existence of tightly bound waters in the loop II region and the unfolding stability of CTs at various temperatures . Deciphering the structure–function relationships for CTs is especially important and interesting since these proteins have a very similar and stable spatial structure, although their activity can seriously vary.…”

Section: Introductionmentioning

confidence: 99%

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Cardiotoxins: Functional Role of Local Conformational Changes

Konshina

Крылов

Efremov

2017

J. Chem. Inf. Model.

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Cardiotoxins (CTs) from snake venoms are a family of homologous highly basic proteins that have extended hydrophobic patterns on their molecular surfaces. CTs are folded into three β-structured loops stabilized by four disulfide bridges. Being well-structured in aqueous solution, most of these proteins are membrane-active, although the exact molecular mechanisms of CT-induced cell damage are still poorly understood. To elucidate the structure-function relationships in CTs, a detailed knowledge of their spatial organization and local conformational dynamics is required. Protein domain motions can be either derived from a set of experimental structures or generated via molecular dynamics (MD). At the same time, traditional clustering algorithms in the Cartesian coordinate space often fail to properly take into account the local large-scale dihedral angle transitions that occur in MD simulations. This is because such perturbations are usually offset by changes in the neighboring dihedrals, thus preserving the overall protein fold. States with a "locally perturbed" backbone were found in experimental 3D models of some globular proteins and have been shown to be functionally meaningful. In this work, the possibility of large-scale dihedral angle transitions in the course of long-term MD in explicit water was explored for three CTs with different membrane activities: CT 1, 2 (Naja oxiana) and CT A3 (Naja atra). Analysis of the MD-derived distributions of backbone torsion angles revealed several important common and specific features in the structural/dynamic behavior of these proteins. First, large-amplitude transitions were detected in some residues located in the functionally important loop I region. The K5/L6 pair of residues was found to induce a perturbation of the hydrophobic patterns on the molecular surface of CTs-reversible breaking of a large nonpolar zone ("bottom") into two smaller ones and their subsequent association. Second, the characteristic sizes of these patterns perfectly coincided with the dimensions of the nonpolar zones on the surfaces of model two-component (zwitterionic/anionic) membranes. Taken together with experimental data on the CT-induced leakage of fluorescent dye from such membranes, these results allowed us to formulate a two-stage mechanism of CT-membrane binding. The principal finding of this study is that even local conformational dynamics of CTs can seriously affect their functional activity via a tuning of the membrane binding site - specific "hot spots" (like the K5/L6 pair) in the protein structure.

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