Biology subjects

MacAinsh, M.

Publications and source records attributed to MacAinsh, M..

5 recordsLinked to original sources

bioRxiv2025

DIRseq: a method for predicting drug-interacting residues of intrinsically disordered proteins from sequences

Intrinsically disordered proteins (IDPs) are now well-recognized as drug targets. Identifying drug-interacting residues is valuable for both optimizing compounds and elucidating the mechanism of action. Currently, NMR chemical shift perturbation and all-atom molecular dynamics (MD) simulations are the primary tools for this purpose. Here we present DIRseq, a fast method for predicting drug-interacting residues from the amino-acid sequence. All residues contribute to the propensity of a particular residue to be drug-interacting; the contributing factor of each residue has an amplitude that is determined by its amino-acid type and attenuates with increasing sequence distance from the particular residue. DIRseq predictions match well with drug-interacting residues identified by NMR chemical shift perturbation and other methods, including residues L22WK24 and Q52WFT55 in the tumor suppressor protein p53. These successes augur well for deciphering the sequence code for IDP-drug binding. DIRseq is available as a web server at https://zhougroup-uic.github.io/DIRseq/ and has many applications, such as virtual screening against IDPs and designing IDP fragments for in-depth NMR and MD studies.

biophysics↗

bioRxiv2024

Direct and Indirect Salt Effects on Homotypic Phase Separation

The low-complexity domain of hnRNPA1 (A1-LCD) phase separates in a salt-dependent manner. Unlike many intrinsically disordered proteins (IDPs) whose phase separation is suppressed by increasing salt concentrations, the phase separation of A1-LCD is promoted by > 100 mM NaCl. To investigate the atypical salt effect on A1-LCD phase separation, we carried out all-atom molecular dynamics simulations of systems comprising multiple A1-LCD chains at NaCl concentrations from 50 to 1000 mM NaCl. The ions occupy first-shell as well as more distant sites around the IDP chains, with Arg sidechains and backbone carbonyls the favored partners of Cl- and Na+, respectively. They play two direct roles in driving A1-LCD condensation. The first is to neutralize the high net charge of the protein (+9) by an excess of bound Cl- over Na+; the second is to bridge between A1-LCD chains, thereby fortifying the intermolecular interaction networks in the dense phase. At high concentrations, NaCl also indirectly strengthens {pi}-{pi}, cation-{pi}, and amino-{pi} interactions, by drawing water away from the interaction partners. Therefore, at low salt, A1-LCD is prevented from phase separation by net charge repulsion; at intermediate concentrations, NaCl neutralizes enough of the net charge while also bridging IDP chains to drive phase separation. This drive becomes even stronger at high salt due to strengthened {pi}-type interactions. Based on this understanding, four classes of salt dependence of IDP phase separation can be predicted from amino-acid composition.

biophysics↗

bioRxiv2022

Partial Mimicry of the Microtubule Binding of Tau by Its Membrane Binding

Tau, as typical of intrinsically disordered proteins (IDPs), binds to multiple targets including microtubules and acidic membranes. The latter two surfaces are both highly negatively charged, raising the prospect of mimicry in their binding by tau. The tau-microtubule complex was recently determined by cryo-EM. Here we used molecular dynamics simulations to characterize the dynamic binding of tau K19 to an acidic membrane. This IDP can be divided into three repeats, each containing an amphipathic helix. The three amphipathic helices, along with flanking residues, tether the protein to the membrane interface. The separation between and membrane positioning of the amphipathic helices in the simulations are validated by published EPR data. The membrane contact probabilities of individual residues in tau show both similarities to and distinctions from native contacts with microtubules. In particular, a Lys that is conserved among the repeats forms similar interactions with membranes and with microtubules, as does a conserved Val. This partial mimicry facilitates both the membrane anchoring of microtubules by tau and the transfer of tau from membranes to microtubules.

biophysics↗

bioRxiv2022

Sequence-Dependent Backbone Dynamics of Intrinsically Disordered Proteins

For intrinsically disordered proteins (IDPs), a pressing question is how sequence codes for function. Dynamics serves as a crucial link, reminiscent of the role of structure in sequence-function relations of structured proteins. To define general rules governing sequence-dependent backbone dynamics, we carried out long molecular dynamics simulations of eight IDPs. Blocks of residues exhibiting large amplitudes in slow dynamics are rigidified by local inter-residue interactions or secondary structures. A long region or an entire IDP can be slowed down by long-range contacts or secondary- structure packing. On the other hand, glycines promote fast dynamics and either demarcate rigid blocks or facilitate multiple modes of local and long-range inter-residue interactions. The sequence-dependent backbone dynamics endows IDPs with versatile response to binding partners, with some blocks recalcitrant while others readily adapting to intermolecular interactions.

biophysics↗

bioRxiv2021

Removing Thermostat Distortions of Protein Dynamics in Constant-Temperature Molecular Dynamics Simulations

Molecular dynamics simulations are widely used to determine equilibrium and dynamic properties of proteins. Nearly all simulations nowadays are carried out at constant temperature, with a Langevin thermostat among the most widely used. Thermostats distort protein dynamics, but whether or how such distortions can be corrected has long been an open question. Here we show that constant-temperature simulations with a Langevin thermostat dilate protein dynamics and present a correction scheme to remove the dynamic distortions. Specifically, ns-scale time constants for overall rotation are dilated significantly but sub-ns time constants for internal motions are dilated modestly, while all motional amplitudes are unaffected. The correction scheme involves contraction of the time constants, with the contraction factor a linear function of the time constant to be corrected. The corrected dynamics of eight proteins are validated by NMR data for rotational diffusion and for backbone amide and side-chain methyl relaxation. The present work demonstrates that, even for complex systems like proteins with dynamics spanning multiple timescales, one can predict how thermostats distort protein dynamics and remove such distortions. The correction scheme will have wide applications, facilitating force-field parameterization and propelling simulations to be on par with NMR and other experimental techniques in determining dynamic properties of proteins. TOC graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/447619v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@1aa72e8org.highwire.dtl.DTLVardef@15e0a4eorg.highwire.dtl.DTLVardef@f6c41borg.highwire.dtl.DTLVardef@c4e8e8_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗