2D Zernike polynomial expansion: Finding the protein-protein binding regions

Milanetti, Edoardo; Miotto, Mattia; Rienzo, Lorenzo Di; Monti, Michele; Gosti, Giorgio; Ruocco, G.

doi:10.1016/j.csbj.2020.11.051

Cited by 33 publications

(79 citation statements)

References 58 publications

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“…In particular, we first determine the distance decrease of the Zernike descriptors (see Section 4 ) for a pair of interacting binding sites as compared to the distance between random patches. Our unsupervized method can recognize the binding regions with respect to random patches with an area under the ROC (receiver operating characteristic) curve (AUC) of 0.70 when considering patches of radius 6 Å (see ( Milanetti et al, 2021 )). Furthermore, the low computational time needed for the calculation of the 2D-Zernike descriptors allows an extensive sampling of the surfaces of a pair of proteins in a complex.…”

Section: Resultsmentioning

confidence: 99%

“…As an example, we report in Figure 1 the protocol of our method for a specific case (PDB code: 3B0F), where this procedure clearly identifies the binding regions of the two proteins (see Section 4 and Ref ( Milanetti et al, 2021 ). for further details).…”

Section: Resultsmentioning

confidence: 99%

“…Here, we adopt a recently developed and parameter-free method to efficiently describe the shape of molecular surfaces with the 2D-Zernike formalism ( Milanetti et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

In-Silico Evidence for a Two Receptor Based Strategy of SARS-CoV-2

Milanetti

Miotto

Rienzo

et al. 2021

Front. Mol. Biosci.

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We propose a computational investigation on the interaction mechanisms between SARS-CoV-2 spike protein and possible human cell receptors. In particular, we make use of our newly developed numerical method able to determine efficiently and effectively the relationship of complementarity between portions of protein surfaces. This innovative and general procedure, based on the representation of the molecular isoelectronic density surface in terms of 2D Zernike polynomials, allows the rapid and quantitative assessment of the geometrical shape complementarity between interacting proteins, which was unfeasible with previous methods. Our results indicate that SARS-CoV-2 uses a dual strategy: in addition to the known interaction with angiotensin-converting enzyme 2, the viral spike protein can also interact with sialic-acid receptors of the cells in the upper airways.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

In-Silico Evidence for a Two Receptor Based Strategy of SARS-CoV-2

Milanetti

Miotto

Rienzo

et al. 2021

Front. Mol. Biosci.

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“…After all surface points are associated with their binding propensity, we performed a smoothing process to highlight the signal in specif regions characterized mostly by low distance values. In this process each point is associated with the mean value of the points in its neighborhood: the basic idea is that the interacting region should be made up mostly of elements with high complementarity and therefore a high average value of binding propensity values (see Milanetti et al (2020b , a) for further details). For both the patch definition and the smoothing process we adopted a sphere radius of 6 Å .…”

Section: Methodsmentioning

confidence: 99%

Molecular Mechanisms Behind Anti SARS-CoV-2 Action of Lactoferrin

Miotto

Rienzo

Bò

et al. 2021

Front. Mol. Biosci.

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Despite the huge effort to contain the infection, the novel SARS-CoV-2 coronavirus has rapidly become pandemic, mainly due to its extremely high human-to-human transmission capability, and a surprisingly high viral charge of symptom-less people. While the seek for a vaccine is still ongoing, promising results have been obtained with antiviral compounds. In particular, lactoferrin is regarded to have beneficial effects both in preventing and soothing the infection. Here, we explore the possible molecular mechanisms with which lactoferrin interferes with SARS-CoV-2 cell invasion, preventing attachment and/or entry of the virus. To this aim, we search for possible interactions lactoferrin may have with virus structural proteins and host receptors. Representing the molecular iso-electron surface of proteins in terms of 2D-Zernike descriptors, we 1) identified putative regions on the lactoferrin surface able to bind sialic acid present on the host cell membrane, sheltering the cell from the virus attachment; 2) showed that no significant shape complementarity is present between lactoferrin and the ACE2 receptor, while 3) two high complementarity regions are found on the N- and C-terminal domains of the SARS-CoV-2 spike protein, hinting at a possible competition between lactoferrin and ACE2 for the binding to the spike protein.

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“…To identify these binding regions, we use a method we have recently developed based on the mathematical formalism of the Zernike polynomial in two dimensions [ 22 , 23 ]. The method, characterized by a low computational cost compared to the commonly used version in three dimensions, examines portions of the molecular surface of two hypothetically interacting protein structures in terms of their local shape complementarity.…”

Section: Introductionmentioning

confidence: 99%

A Computational Approach to Investigate TDP-43 RNA-Recognition Motif 2 C-Terminal Fragments Aggregation in Amyotrophic Lateral Sclerosis

et al. 2021

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Many of the molecular mechanisms underlying the pathological aggregation of proteins observed in neurodegenerative diseases are still not fully understood. Among the aggregate-associated diseases, Amyotrophic Lateral Sclerosis (ALS) is of relevant importance. In fact, although understanding the processes that cause the disease is still an open challenge, its relationship with protein aggregation is widely known. In particular, human TDP-43, an RNA/DNA binding protein, is a major component of the pathological cytoplasmic inclusions observed in ALS patients. Indeed, the deposition of the phosphorylated full-length TDP-43 in spinal cord cells has been widely studied. Moreover, it has also been shown that the brain cortex presents an accumulation of phosphorylated C-terminal fragments (CTFs). Even if it is debated whether the aggregation of CTFs represents a primary cause of ALS, it is a hallmark of TDP-43 related neurodegeneration in the brain. Here, we investigate the CTFs aggregation process, providing a computational model of interaction based on the evaluation of shape complementarity at the molecular interfaces. To this end, extensive Molecular Dynamics (MD) simulations were conducted for different types of protein fragments, with the aim of exploring the equilibrium conformations. Adopting a newly developed approach based on Zernike polynomials, able to find complementary regions in the molecular surface, we sampled a large set of solvent-exposed portions of CTFs structures as obtained from MD simulations. Our analysis proposes and assesses a set of possible association mechanisms between the CTFs, which could drive the aggregation process of the CTFs. To further evaluate the structural details of such associations, we perform molecular docking and additional MD simulations to propose possible complexes and assess their stability, focusing on complexes whose interacting regions are both characterized by a high shape complementarity and involve β3 and β5 strands at their interfaces.

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2D Zernike polynomial expansion: Finding the protein-protein binding regions

Abstract: Graphical abstract

Cited by 33 publications

References 58 publications

In-Silico Evidence for a Two Receptor Based Strategy of SARS-CoV-2

In-Silico Evidence for a Two Receptor Based Strategy of SARS-CoV-2

Molecular Mechanisms Behind Anti SARS-CoV-2 Action of Lactoferrin

A Computational Approach to Investigate TDP-43 RNA-Recognition Motif 2 C-Terminal Fragments Aggregation in Amyotrophic Lateral Sclerosis

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