The Weighted Histogram Analysis Method (WHAM) is a standard technique used to compute potentials of mean force (PMFs) from a set of umbrella sampling simulations. Here, we present a new WHAM implementation, termed g_wham, which is distributed freely with the GROMACS molecular simulation suite. g_wham estimates statistical errors using the technique of bootstrap analysis. Three bootstrap methods...

MLN4924 is an experimental cancer drug known as inhibitor of NEDD8-activating enzyme (NAE). This anti-tumor candidate is a selective small-molecule inhibitor of NAE which is conjugated to cullin protein on Cullin-RING ligases (CRLs). This covalent modification actives cullin complex to recruit an ubiquitin-charged E2 and leads to downstream target protein polyubiquitination and proteasomal degr...

Plecanatide is a recently developed guanylate cyclase-C (GC-C) agonist and the first uroguanylin analog designed to treat chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C). GC-C receptors are found across the length of the intestines and are thought to play a key role in fluid regulation and electrolyte balance. Ligands of the GC-C receptor include end...

The drug discovery process has been deeply transformed recently by the use of computational ligand-based or structure-based methods, helping the lead compounds identification and optimization, and finally the delivery of new drug candidates more quickly and at lower cost. Structure-based computational methods for drug discovery mainly involve ligand-protein docking and rapid binding free energy...

Single amino acid substitutions in the globin chain are the most common forms of genetic variations that produce hemoglobinopathies--the most widespread inherited disorders worldwide. Several hemoglobinopathies result from homozygosity or compound heterozygosity to beta-globin (HBB) gene mutations, such as that producing sickle cell hemoglobin (HbS), HbC, HbD and HbE. Several of these mutations...

Introduced by Duane and his co-workers in 1987, the hybrid Monte Carlo (HMC) proved itself to be both an efficient sampling device and an effective realization of a stochastic thermostat. The method combines the best features of two well established simulation techniques, molecular dynamics and Monte Carlo. Among its drawbacks are inability to reproduce dynamical properties of a system, and lac...

The advantages of distributing workloads and utilizing multiple distributed resources are now well established. The type and degree of heterogeneity of distributed resources is increasing, and thus determining how to distribute the workloads becomes increasingly difficult, in particular with respect to the selection of suitable resources. We formulate and investigate the resource selection prob...