arXiv subjects

Wieslaw Nowak

Publications and source records attributed to Wieslaw Nowak.

3 recordsLinked to original sources

arXiv2019

Memetic Algorithms for Ligand Expulsion from Protein Cavities

Ligand diffusion through proteins is a fundamental process governing biological signaling and enzymatic catalysis. The complex topology of protein tunnels results in difficulties with computing ligand escape pathways by standard molecular dynamics (MD) simulations. Here, two novel methods for searching of ligand exit pathways and cavity exploration are proposed: memory random acceleration MD (mRAMD), and memetic algorithms (MA). In mRAMD, finding exit pathways is based on a non-Markovian biasing that is introduced to optimize the unbinding force. In MA, hybrid learning protocols are exploited to predict optimal ligand exit paths. The methods are tested on three proteins with increasing complexity of tunnels: M2 muscarinic receptor, nitrile hydratase, and cytochrome P450cam. In these cases, the proposed methods outperform standard techniques that are used currently to find ligand egress pathways. The proposed approach is general and appropriate for accelerated transport of an object through a network of protein tunnels.

physics.chem-ph↗

arXiv2015

Entropic measure to prevent energy over-minimization in molecular dynamics simulations

This work examines the impact of energy over-minimization on an ensemble of biological molecules subjected to the potential energy minimization procedure in vacuum. In the studied structures, long potential energy minimization stage leads to an increase of the main- and side-chain entropies in proteins. We show that such over-minimization may diverge the protein structures from the near-native attraction basin which possesses a minimum of free energy. We propose a measure based on the Pareto front of total entropy for quality assessment of minimized protein conformation. This measure may help in selection of adequate number of energy minimization steps in protein modelling and, thus, in preservation of the near-native protein conformation.

physics.bio-ph↗

arXiv2011

Molecular jamming - the cystine slipknot mechanical clamp in all-atom simulations

A recent survey of 17 134 proteins has identified a new class of proteins which are expected to yield stretching induced force-peaks in the range of 1 nN. Such high force peaks should be due to forcing of a slip-loop through a cystine ring, i.e. by generating a cystine slipknot. The survey has been performed in a simple coarse grained model. Here, we perform all-atom steered molecular dynamics simulations on 15 cystine knot proteins and determine their resistance to stretching. In agreement with previous studies within a coarse grained structure based model, the level of resistance is found to be substantially higher than in proteins in which the mechanical clamp operates through shear. The large stretching forces arise through formation of the cystine slipknot mechanical clamp and the resulting steric jamming. We elucidate the workings of such a clamp in an atomic detail. We also study the behavior of five top strength proteins with the shear-based mechanostability in which no jamming is involved. We show that in the atomic model, the jamming state is relieved by moving one amino acid at a time and there is a choice in the selection of the amino acid that advances the first. In contrast, the coarse grained model also allows for a simultaneous passage of two amino acids.

q-bio.BM↗