Molecular recognition of metabotropic glutamate receptor type 1 (mGluR1): synergistic understanding with free energy perturbation and linear response modeling.

Metabotropic glutamate receptors (mGluRs) constitute an important family of the G-protein coupled receptors. Due to their widespread distribution in the central nervous system (CNS), these receptors are attractive candidates for understanding the molecular basis of various cognitive processes as well as for designing inhibitors for relevant psychiatric and neurological disorders. Despite many studies on drugs targeting the mGluR receptors to date, the molecular level details on the ligand binding dynamics still remain unclear.

Population differentiation of southern Indian male lineages correlates with agricultural expansions predating the caste system.

Previous studies that pooled Indian populations from a wide variety of geographical locations, have obtained contradictory conclusions about the processes of the establishment of the Varna caste system and its genetic impact on the origins and demographic histories of Indian populations. To further investigate these questions we took advantage that both Y chromosome and caste designation are paternally inherited, and genotyped 1,680 Y chromosomes representing 12 tribal and 19 non-tribal (caste) endogamous populations from the predominantly Dravidian-speaking Tamil Nadu state in the southernmost part of India. Tribes and castes were both characterized by an overwhelming proportion of putatively Indian autochthonous Y-chromosomal haplogroups (H-M69, F-M89, R1a1-M17, L1-M27, R2-M124, and C5-M356; 81% combined) with a shared genetic heritage dating back to the late Pleistocene (10-30 Kya), suggesting that more recent Holocene migrations from western Eurasia contributed <20% of the male lineages.

Free energy simulations reveal a double mutant avian H5N1 virus hemagglutinin with altered receptor binding specificity.

Historically, influenza pandemics have been triggered when an avian influenza virus or a human/avian reassorted virus acquires the ability to replicate efficiently and become transmissible in the human population. Most critically, the major surface glycoprotein hemagglutinin (HA) must adapt to the usage of human-like (alpha-2,6-linked) sialylated glycan receptors. Therefore, identification of mutations that can switch the currently circulating H5N1 HA receptor binding specificity from avian to human might provide leads to the emergence of pandemic H5N1 viruses.

Single mutation induced H3N2 hemagglutinin antibody neutralization: a free energy perturbation study.

The single mutation effect on the binding affinity of H3N2 viral protein hemagglutinin (HA) with the monoclonical antibody fragment (Fab) is studied in this paper using the free energy perturbation (FEP) simulations. An all-atom protein model with explicit solvents is used to perform an aggregate of several microsecond FEP molecular dynamics simulations. A recent experiment shows that a single mutation in H3N2 HA, T131I, increases the antibody-antigen dissociation constant Kd by a factor of approximately 4000 (equivalent to a binding affinity decrease of approximately 5 kcal/mol), thus introducing an escape of the antibody (Ab) neutralization.

Maximum-likelihood estimation of site-specific mutation rates in human mitochondrial DNA from partial phylogenetic classification.

The mitochondrial DNA hypervariable segment I (HVS-I) is widely used in studies of human evolutionary genetics, and therefore accurate estimates of mutation rates among nucleotide sites in this region are essential. We have developed a novel maximum-likelihood methodology for estimating site-specific mutation rates from partial phylogenetic information, such as haplogroup association. The resulting estimation problem is a generalized linear model, with a nonstandard link function.

Y-chromosomal diversity in Lebanon is structured by recent historical events.

Lebanon is an eastern Mediterranean country inhabited by approximately four million people with a wide variety of ethnicities and religions, including Muslim, Christian, and Druze. In the present study, 926 Lebanese men were typed with Y-chromosomal SNP and STR markers, and unusually, male genetic variation within Lebanon was found to be more strongly structured by religious affiliation than by geography. We therefore tested the hypothesis that migrations within historical times could have contributed to this situation.

Destruction of long-range interactions by a single mutation in lysozyme.

We propose a mechanism, based on a > or =10-micros molecular dynamics simulation, for the surprising misfolding of hen egg-white lysozyme caused by a single mutation (W62G). Our simulations of the wild-type and mutant lysozymes in 8 M urea solution at biological temperature (with both pH 2 and 7) reveal that the mutant structure is much less stable than that of the wild type, with the mutant showing larger fluctuations and less native-like contacts. Analysis of local contacts reveals that the Trp-62 residue is the key to a cooperative long-range interaction within the wild type, where it acts like a bridge between two neighboring basic residues.

Thermal denaturing of mutant lysozyme with both the OPLSAA and the CHARMM force fields.

Biomolecular simulations enabled by massively parallel supercomputers such as BlueGene/L promise to bridge the gap between the currently accessible simulation time scale and the experimental time scale for many important protein folding processes. In this study, molecular dynamics simulations were carried out for both the wild-type and the mutant hen lysozyme (TRP62GLY) to study the single mutation effect on lysozyme stability and misfolding. Our thermal denaturing simulations at 400-500 K with both the OPLSAA and the CHARMM force fields show that the mutant structure is indeed much less stable than the wild-type, which is consistent with the recent urea denaturing experiment (Dobson et al.

Spatial profiling of protein hydrophobicity: native vs. decoy structures.

A recent study of 30 soluble globular protein structures revealed a quasi-invariant called the hydrophobic ratio. This invariant, which is the ratio of the distance at which the second order hydrophobic moment vanished to the distance at which the zero order moment vanished, was found to be 0.75 +/- 0.

Principles of mucin architecture: structural studies on synthetic glycopeptides bearing clustered mono-, di-, tri-, and hexasaccharide glycodomains.

The structural characteristics of a mucin glycopeptide motif derived from the N-terminal fragment STTAV of the cell surface glycoprotein CD43 have been investigated by NMR. In this study, a series of molecules prepared by total synthesis were examined, consisting of the peptide itself, three glycopeptides having clustered sites of alpha-O-glycosylation on the serine and threonine side chains with the Tn, TF, and STF carbohydrate antigens, respectively, and one with the beta-O-linked TF antigen. Additionally, a glycopeptide having the sequence SSSAVAV, triglycosylated with the Le(y) epitope, was investigated.