Biology subjects

Mansbach, R.

Publications and source records attributed to Mansbach, R..

5 recordsLinked to original sources

bioRxiv2026

Conformational and molecular interactions of small molecules targeting the SAM-I riboswitch

There has been a surge in antibiotic resistance in recent years, making traditional antibiotics less effective against key pathogens. RNA has recently emerged as a potential target for antibiotics due to its involvement in crucial microbial functions. It is possible to expand the range of therapeutic targets by using RNA-based therapies, but it remains necessary to improve the molecular-level understanding of interactions between RNA and known and potential binders. The SAM-I riboswitch, which controls the transcriptional termination of gene expression involved in sulfur metabolism in most bacteria, is an excellent ligand target. Thus, understanding its behavior with and without ligand complexes would be very helpful for drug design applications. In this manuscript, we studied the interactions between the SAM-I riboswitch and its natural ligand, SAM, which controls riboswitch function, and compared those interactions to its interactions with the very similar small molecular SAH, which does not control riboswitch function, and to its interactions with a potential binder JS4, identified via virtual screening. From our simulations, we gain a deeper understanding of small molecule interactions with the SAM-I riboswitch. The results reveal how differently the small molecules (SAM, SAH and JS4) bind to and potentially induce conformational changes in the riboswitch. Our findings offer valuable insight into the molecular mechanisms underlying riboswitch RNA-ligand interactions for the design of more effective RNA-targeting therapeutics.

molecular biology↗

bioRxiv2025

Revealing pH-dependent antimicrobial peptide, GL13K, characteristics: A constant pH molecular dynamics study

Membrane-active antimicrobial peptides (AMPs) are a promising potential solution to combat rising antimicrobial resistance (AMR) due to their selective interaction with negatively charged bacterial membranes, but their behavior is controlled by their charge states, which in turn depend on the local pH in which they find themselves. In this study, we employ constant pH molecular dynamics (CpHMD) simulations to investigate the pH-dependent behavior of a 13-residue-long positively charge AMP, GL13K, focusing on the deprotonation states of lysine residues in a single GL13K AMP and their impact on its structural dynamics. We determine pKa values of the critical lysine residues and show that the last lysine located near the C-terminus (LYS11) has a significant deprotonation difference with other lysine residues. We observe that increasing the pH results in changes in the metastable conformational states including collapse of the peptide and highlight the stabilization of a potentially therapeutically-relevant {beta} hairpin configuration in pH levels leading to partial protonation of the lysines. Overall, our study shows the pH-dependent conformational dynamics and pKa variations of lysine residues in the GL13K antimicrobial peptide, providing critical insights into its structural behavior in solution. These findings establish a necessary rigorous foundation for further exploration of GL13K in more complex systems, advancing its potential development as an antimicrobial agent.

biophysics↗

bioRxiv2023

Identification of residues potentially involved in optical shifts in the water-soluble chlorophyll-a binding protein through molecular dynamics simulations

Reversible light- and thermally-induced spectral shifts are universally observed in a wide variety of pigment-protein complexes, at temperatures ranging from cryogenic to ambient. They can be observed either directly, in single-molecule spectroscopy experiments, or via non-photochemical spectral hole burning. These shifts are important to understand, for example, to gain a clearer picture of the primary processes of photosynthesis, or of general features of the protein energy landscapes. In this article, we have employed large-scale molecular dynamics simulations of a prototypical pigment-protein complex to better understand these shifts at a molecular scale. Although multiple mechanisms have been proposed over the years, no verification of these proposals via MD simulations has thus far been performed; our work represents the first step in this direction. The common requirement for all these mechanisms is the presence of doublewell (or multiple-well) features of the protein energy landscapes. In this work, from large-scale molecular dynamics simulations of the Water-Soluble Chlorophyll-binding Protein complex, we identified side chain rotations of certain amino acid residues as likely candidates for relevant multi-well landscape features. The protein free energy landscapes associated with side chain rotations feature energy barriers of around 1100- 1600 cm-1, in agreement with optical spectroscopy results, with the most promising residue type associated with experimental signatures being serine, which possesses a symmetric landscape and moment of inertia of a relevant magnitude.

biophysics↗

bioRxiv2021

Network analysis outlines strengths and weaknesses of emerging SARS-CoV-2 Spike variants

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has triggered myriad efforts to dissect and understand the structure and dynamics of this complex pathogen. The Spike glycoprotein of SARS-CoV-2 has received special attention as it is the means by which the virus enters the human host cells. The N-terminal domain (NTD) is one of the targeted regions of the Spike protein for therapeutics and neutralizing antibodies against COVID-19. Though its function is not well-understood, the NTD is reported to acquire mutations and deletions that can accelerate the evolutionary adaptation of the virus driving antibody escape. Cellular processes are known to be regulated by complex interactions at the molecular level, which can be characterized by means of a graph representation facilitating the identification of key residues and critical communication pathways within the molecular complex. From extensive all-atom molecular dynamics simulations of the entire Spike for the wild-type and the dominant variant, we derive a weighted graph representation of the protein in two dominant conformations of the receptor-binding-domain; all-down and one-up. We implement graph theory techniques to characterize the relevance of specific residues at facilitating roles of communication and control, while uncovering key implications for fitness and adaptation. We find that many of the reported high-frequency mutations tend to occur away from the critical residues highlighted by our graph theory analysis, implying that these mutations tend to avoid targeting residues that are most critical for protein allosteric communication. We propose that these critical residues could be candidate targets for novel antibody therapeutics. In addition, our analysis provides quantitative insights of the critical role of the NTD and furin cleavage site and their wide-reaching influence over the protein at large. Many of our conclusions are supported by empirical evidence while others point the way towards crucial simulation-guided experiments.

molecular biology↗

bioRxiv2021

Exploring the role of glycans in the interaction of SARS-CoV-2 RBD and human receptor ACE2

COVID-19 is a highly infectious respiratory disease caused by the novel coronavirus SARS-CoV-2. It has become a global pandemic and its frequent mutations may pose new challenges for vaccine design. During viral infection, the Spike RBD of SARS-CoV-2 binds the human host cell receptor ACE2, enabling the virus to enter the host cell. Both the Spike and ACE2 are densely glycosylated, and it is unclear how distinctive glycan types may modulate the interaction of RBD and ACE2. Detailed understanding of these determinants is key for the development of novel therapeutic strategies. To this end, we perform extensive all-atom simulations of the (i) RBD-ACE2 complex without glycans, (ii) RBD-ACE2 with oligomannose MAN9 glycans in ACE2, and (iii) RBD-ACE2 with complex FA2 glycans in ACE2. These simulations identify the key residues at the RBD-ACE2 interface that form contacts with higher probabilities, thus providing a quantitative evaluation that complements recent structural studies. Notably, we find that this RBD-ACE2 contact signature is not altered by the presence of different glycoforms, suggesting that RBD-ACE2 interaction is robust. Applying our simulated results, we illustrate how the recently prevalent N501Y mutation may alter specific interactions with host ACE2 that facilitate the virus-host binding. Furthermore, our simulations reveal how the glycan on Asn90 of ACE2 can play a distinct role in the binding and unbinding of RBD. Finally, an energetics analysis shows that MAN9 glycans on ACE2 decrease RBD-ACE2 affinity, while FA2 glycans lead to enhanced binding of the complex. Together, our results provide a more comprehensive picture of the detailed interplay between virus and human receptor, which is much needed for the discovery of effective treatments that aim at modulating the physical-chemical properties of this virus.

biophysics↗