Article
Biochemistry & Molecular Biology
Elias Khayat, Bryan M. Delfing, Xavier Laracuente, Audrey Olson, Christopher Lockhart, Dmitri K. Klimov
Summary: The Lys28 acetylation of the Afi peptide has significant impact on its binding to the lipid bilayer. Acetylation strengthens the hydrophobic moment and promotes helical structure of the peptide, but reduces its affinity to the DMPC bilayer. Acetylation also facilitates aggregation of the peptide into low-molecular-weight oligomers.
ACS CHEMICAL NEUROSCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Ai Shinobu, Suyong Re, Yuji Sugita
Summary: Molecular dynamics (MD) simulations are used to study biological processes, but conventional methods are not effective for slow dynamics. Researchers applied a two-dimensional replica-exchange MD method and optimized the simulation protocols to achieve accurate results and good random sampling.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Piotr Chyzy, Marta Kulik, Suyong Re, Yuji Sugita, Joanna Trylska
Summary: Short, structured fragments of non-coding mRNA may act as molecular switches upon binding specific ligands, regulating the translation of proteins encoded downstream this mRNA sequence. The study reveals that nucleobase mutations in the riboswitch can significantly affect the affinity and efficiency of ligand regulation, with specific mutations altering the binding site position of neomycin and increasing its flexibility.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Xianshi Liu, Xuhua Li, Qin Qiao, Fangying Li, Guanghong Wei
Summary: This study demonstrates that pathogenic mutations enhance the formation of β-barrel structures in the TDP-43307-319 hexamer. The enhanced structures are stabilized by increased intermolecular interactions caused by the mutations. These findings provide insight into the molecular determinants underlying the neurotoxicity of TDP-43 protein in amyotrophic lateral sclerosis (ALS).
ACS CHEMICAL NEUROSCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Xianshi Liu, Xuhua Li, Qin Qiao, Fangying Li, Guanghong Wei
Summary: It is found that ALS-linked mutants A315T and A315E of TDP-43 can self-assemble into oligomers including tetramers, hexamers, and octamers, with hexamers potentially forming g-barrel structures. Mutants have a higher propensity to form g-barrels compared to the wild type, explaining their enhanced neurotoxicity.
ACS CHEMICAL NEUROSCIENCE
(2023)
Article
Chemistry, Multidisciplinary
Bryan A. Raubenolt, Steven W. Rick
Summary: This paper presents a replica-exchange method for overcoming the amide bond sampling problem in polypeptoids. The method allows for easy access to both cis and trans conformations and enhances sampling for other coordinates. The results show that the conformation of the peptoids depends on the side chain and potential model.
JOURNAL OF COMPUTATIONAL CHEMISTRY
(2022)
Article
Chemistry, Physical
Tiffani Hui, Marc L. L. Descoteaux, Jiayuan Miao, Yu-Shan Lin
Summary: Cyclic peptides have potential as therapeutics, but designing them from scratch is challenging. Most cyclic peptides adopt multiple conformations in water, making it difficult to rationalize their design. Previous research showed that machine learning models trained on molecular dynamics simulations can predict structural ensembles of cyclic pentapeptides. Now, researchers have improved these models to successfully predict the structural ensembles of cyclic hexapeptides by incorporating complex nonlinear interaction patterns using convolutional neural networks and graph neural networks.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Biochemistry & Molecular Biology
Lorenzo Casbarra, Piero Procacci
Summary: The study demonstrates that Autodock4 performs surprisingly well in absolute binding free energy predictions, outperforming expensive molecular dynamics or quantum chemistry techniques, with an extremely favorable cost-benefit ratio. Interesting features of Autodock4 predictions are revealed, providing valuable insights on the overall reliability of docking screening campaigns in drug discovery projects.
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
(2021)
Article
Chemistry, Multidisciplinary
Xiaorong Liu, Xiping Gong, Jianhan Chen
Summary: Efficient sampling of protein conformational space is crucial for quantitative simulations. The MSES-IT method allows independent control of atomic and CG simulation temperatures, improving both sampling efficiency and structural transition rates. This new approach facilitates faster reversible transitions at the atomic level, leading to significant improvements in generating converged conformational ensembles compared to the original MSES scheme.
JOURNAL OF COMPUTATIONAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Sandro Bottaro, Giovanni Bussi, Kresten Lindorff-Larsen
Summary: This study predicted the structure and dynamics of RNA stem loops in the 5'UTR of the SARS-CoV-2 genome using extensive molecular dynamics simulations, revealing rich dynamics and specific structural rearrangements. These findings could provide insights into the structural features and functional roles of RNA molecules.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Biochemistry & Molecular Biology
Iga Biskupek, Cezary Czaplewski, Justyna Sawicka, Emilia Ilowska, Maria Dzierzynska, Sylwia Rodziewicz-Motowidlo, Adam Liwo
Summary: The UNited RESidue (UNRES) model was used to study the aggregation behavior of 20 peptides with different lengths. The majority of peptides showed inter-strand beta-sheet formation, except for glutamine- and asparagine-rich peptides, which require modification of the UNRES model.
Article
Chemistry, Multidisciplinary
Anji Babu Kapakayala, Nisanth N. Nair
Summary: In this study, a new hybrid method combining WSMTD and REST2 is proposed to speed up conformational sampling and free energy calculation. The method employs a divide-and-conquer strategy to independently sample high-dimensional slices of a free energy surface and enhance sampling of slow degrees of freedom through replica exchange. The combined simulations are used to compute probability distributions of CVs and obtain the free energy surface with improved accuracy and quick convergence.
JOURNAL OF COMPUTATIONAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Yu Zou, Lulu Guan
Summary: This study utilized molecular dynamics simulations to demonstrate that acetylation of K280 enhances the aggregation capability of PHF6* peptides, increasing their beta-sheet structure propensity and inter-molecular interactions. This leads to more ordered beta-sheet-rich conformations of the PHF6* assemblies and decreases structural diversity, ultimately promoting the aggregation of PHF6*.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Article
Chemistry, Physical
Rajeswari Appadurai, Jaya Krishna Koneru, Massimiliano Bonomi, Paul Robustelli, Anand Srivastava
Summary: In this study, t-SNE technique is used to cluster the conformations of intrinsically disordered proteins (IDPs) and visualize the conformational heterogeneity. The conformations of two disordered proteins, Aβ42 and α-synuclein, in their APO states and when bound to small molecule ligands are analyzed, revealing ordered substates within the IDP ensembles and providing insights into the structural and mechanistic aspects of IDP ligand binding. t-SNE projections preserve local neighborhood information, providing interpretable visualizations of conformational heterogeneity within each ensemble and allowing the quantification of cluster populations and their relative shifts upon ligand binding.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Chemistry, Medicinal
Isabell Louise Grothaus, Giovanni Bussi, Lucio Colombi Ciacchi
Summary: Despite their biological relevance, structure-property relationships in N-glycans are currently not well understood. In this study, a novel enhanced-sampling scheme was developed to explore the highly multidimensional compositional and conformational phase spaces of N-glycans. The results reveal the effect of chemical substitutions on the conformational ensemble of selected glycans and assess the structure-prediction capabilities of commonly used force fields.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Biochemistry & Molecular Biology
Christopher Lockhart, Dmitri K. Klimov
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
(2016)
Article
Chemistry, Medicinal
Christopher Lockhart, Dmitri K. Klimov
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2017)
Article
Biochemical Research Methods
Christopher M. Siwy, Christopher Lockhart, Dmitri K. Klimov
PLOS COMPUTATIONAL BIOLOGY
(2017)
Article
Multidisciplinary Sciences
Christopher Lockhart, Amy K. Smith, Dmitri K. Klimov
SCIENTIFIC REPORTS
(2019)
Article
Chemistry, Medicinal
Amy K. Smith, Elias Khayat, Christopher Lockhart, Dmitri K. Klimov
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2019)
Article
Chemistry, Medicinal
Christopher Lockhart, Amy K. Smith, Dmitri K. Klimov
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2020)
Article
Chemistry, Physical
Christopher M. Siwy, Bryan M. Delfing, Christopher Lockhart, Amy K. Smith, Dmitri K. Klimov
Summary: The study used all-atom replica-exchange umbrella sampling molecular dynamics simulations to investigate the partitioning of the charged tetrapeptide KLVF and its neutral apolar counterpart VVIA into the blood-brain barrier (BBB) -mimetic bilayer. Despite dissimilar sequences, their permeation shares significant common features, and both peptides experience unfavorable partitioning ruling out passive transport.
JOURNAL OF PHYSICAL CHEMISTRY B
(2021)
Article
Biochemistry & Molecular Biology
Elias Khayat, Christopher Lockhart, Bryan M. Delfing, Amy K. Smith, Dmitri K. Klimov
Summary: Using molecular dynamics simulations, this study investigated the aggregation of oxidized A beta 25-35 peptides mediated by a lipid bilayer and found that oxidation reduces helical propensity and increases backbone fluctuations, leading to destabilization of the dimer interface and decreased aggregation propensity. On the other hand, phosphorylation has an opposite effect, preserving the wild-type aggregation interface and enhancing aggregation propensity.
ACS CHEMICAL NEUROSCIENCE
(2021)
Article
Chemistry, Medicinal
Steven R. Bowers, Dmitri K. Klimov, Christopher Lockhart
Summary: This study investigates the binding mechanism of PGLa to anionic bilayers using molecular dynamics simulations and energy calculations. The results reveal two distinct binding states of PGLa, which require helix rotation. The binding is mainly governed by desolvation and electrostatic interactions, leading to lipid redistribution and thinning of the bilayer.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Biochemistry & Molecular Biology
Elias Khayat, Bryan M. Delfing, Xavier Laracuente, Audrey Olson, Christopher Lockhart, Dmitri K. Klimov
Summary: The Lys28 acetylation of the Afi peptide has significant impact on its binding to the lipid bilayer. Acetylation strengthens the hydrophobic moment and promotes helical structure of the peptide, but reduces its affinity to the DMPC bilayer. Acetylation also facilitates aggregation of the peptide into low-molecular-weight oligomers.
ACS CHEMICAL NEUROSCIENCE
(2023)
Article
Chemistry, Medicinal
James Vergilio, Christopher Lockhart, Dmitri K. Klimov
Summary: Using SREMD model, this study investigated the binding of Alzheimer's Afi10-40 peptides to a lipid bilayer and found that the binding is primarily governed by electrostatic interactions. The study also revealed the formation of helical dimers that induce lipid density voids in the bilayer.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Chemistry, Physical
Bryan M. Delfing, Audrey Olson, Xavier E. Laracuente, Kenneth W. Foreman, Mikell Paige, Kylene Kehn-Hall, Christopher Lockhart, Dmitri K. Klimov
Summary: Although Venezuelan equine encephalitis virus (VEEV) is a life-threatening pathogen, there are currently no FDA-approved antivirals for humans. Experimental studies have identified potential inhibitors of the viral nuclear localization signal (NLS) sequence binding to importin-alpha, but the molecular mechanism of CL6662 inhibition is not well understood.
JOURNAL OF PHYSICAL CHEMISTRY B
(2023)
Meeting Abstract
Biophysics
Christopher Lockhart, Amy K. Smith, Dmitri K. Klimov
BIOPHYSICAL JOURNAL
(2020)
Meeting Abstract
Biophysics
Christopher Lockhart, Dmitri K. Klimov
BIOPHYSICAL JOURNAL
(2017)