抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

NAMD is a parallel molecular dynamics code designed for high-performance simulation of large biomolecular systems. NAMD scales to hundreds of processors on high-end parallel platforms, as well as tens of processors on low-cost commodity clusters, and also runs on individual desktop and laptop computers. NAMD works with AMBER and CHARMM potential functions, parameters, and file formats. This article, directed to novices as well as experts, first introduces concepts and methods used in the NAMD program, describing the classical molecular dynamics force field, equations of motion, and integration methods along with the efficient electrostatics evaluation algorithms employed and temperature and pressure controls used. Features for steering the simulation across barriers and for calculating both alchemical and conformational free energy differences are presented. The motivations for and a roadmap to the internal design of NAMD, implemented in C++ and based on Charm++ parallel objects, are outlined. The factors affecting the serial and parallel performance of a simulation are discussed. Finally, typical NAMD use is illustrated with representative applications to a small, a medium, and a large biomolecular system, highlighting particular features of NAMD, for example, the Tcl scripting language. The article also provides a list of the key features of NAMD and discusses the benefits of combining NAMD with the molecular graphics/sequence analysis software VMD and the grid computing/collaboratory software BioCoRE. NAMD is distributed free of charge with source code at www.ks.uiuc.edu.

/pdf/scalable-molecular-dynamics-with-namd-51o1z7rwp8.pdf

Scalable molecular dynamics with NAMD

/pdf/scalable-molecular-dynamics-with-namd-3j7xyc70g4.pdf

Scalable Molecular Dynamics with NAMD

The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.

https://cdr.lib.unc.edu/downloads/v692t8920

A global reference for human genetic variation.

Statistical method for testing the neutral mutation hypothesis by DNA polymorphism.

Single molecules of DNA can be visualized in solution by epifluorescence microscopy, manipulated and extended by a variety of mechanical, electrical and chemical means as described previously. This has been used to design experiments under an optical microscope, in which DNA molecules are extended by a known force, to determine the elastic response of the molecules, both in the presence and absence of ethidium bromide. It is found that at lower forces (smaller extensions) the molecules behave as entropic springs with a persistence length of 500 angstroms, and that at the ionic strengths used, the intercalation of ethidium bromide does not alter this persistence length, while it appears to elongate the contour length of the molecule by about 30%.© (1991) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

Manipulation of single-DNA molecules and measurements of their elastic properties under an optical microscope

While seemingly straightforward in principle, the reliable estimation of rate constants is seldom easy in practice. Numerous issues, such as the complication of poor reaction coordinates, cause obvious approaches to yield unreliable estimates. When a reliable order parameter is available, the reactive flux theory of Chandler allows the rate constant to be extracted from the plateau region of an appropriate reactive flux correlation function. However, when applied to real data from single- molecule experiments or molecular dynamics simulations, the reactive flux correlation function requires the numerical differentiation of a noisy empirical correlation function, which can result in an unacceptably poor estimate of the rate and pathological dependence on the sampling interval. We present a modified version of this theory which does not require numerical derivatives, allowing rate constants to be robustly estimated from the time-correlation function directly. We illustrate the approach using single-molecule passive force spectroscopy measurements of an RNA hairpin.

A robust approach to estimating rates from time-correlation functions

Una revisión sobre las rayas de hocico largo Zearaja chilensis y Dipturus trachyderma (Rajiformes: Rajidae)

Optical traps or "optical tweezers" have become an indispensable tool in understanding fundamental biological processes. The ability to manipulate and probe individual molecules or molecular complexes has led to a new, more refined understanding of the mechanical properties of the fundamental building blocks of the cell, and of the mechanism by which molecular machines function. The minimization and management of noise are the keys to building a high-resolution optical tweezers. The high degree of stability needed to observe angstrom motions of a biological system places rather stringent requirements on the environment in which the instrument operates. Specifically, environmental noise is a concern when it leads to differential movements of the optical trap relative to the second attachment point of the tether. In this article, we discuss what entails a quiet environment--what sources of noise are relevant and how they affect the instrument--and provide guidelines for choosing an appropriate location for a high-resolution instrument.

High-resolution dual-trap optical tweezers with differential detection: managing environmental noise.

Multi-subunit ring-shaped ATPases are molecular motors that harness chemical free energy to perform vital mechanical tasks such as polypeptide translocation, DNA unwinding, and chromosome segregation. Previously we reported the intersubunit coordination and stepping behavior of the hexameric ring-shaped ATPase SpoIIIE (Liu et al., 2015). Here we use optical tweezers to characterize the motor's mechanochemistry. Analysis of the motor response to external force at various nucleotide concentrations identifies phosphate release as the likely force-generating step. Analysis of SpoIIIE pausing indicates that pauses are off-pathway events. Characterization of SpoIIIE slipping behavior reveals that individual motor subunits engage DNA upon ATP binding. Furthermore, we find that SpoIIIE's velocity exhibits an intriguing bi-phasic dependence on force. We hypothesize that this behavior is an adaptation of ultra-fast motors tasked with translocating DNA from which they must also remove DNA-bound protein roadblocks. Based on these results, we formulate a comprehensive mechanochemical model for SpoIIIE.

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Carlos Bustamante

Papers

Manipulation of single-DNA molecules and measurements of their elastic properties under an optical microscope

A robust approach to estimating rates from time-correlation functions

Una revisión sobre las rayas de hocico largo Zearaja chilensis y Dipturus trachyderma (Rajiformes: Rajidae)

High-resolution dual-trap optical tweezers with differential detection: managing environmental noise.

Mechanochemical coupling and bi-phasic force-velocity dependence in the ultra-fast ring ATPase SpoIIIE